Antiplatelet effects of hydroxychloroquine in patients with systemic lupus erythematosus evaluated by the total thrombus-formation analysis system (T-TAS).

OBJECTIVES: Hydroxychloroquine (HCQ) has been shown to reduce thrombotic events in patients with SLE. However, the antiplatelet effects of HCQ are only supported by the platelet aggregation assay, which is a non-physiological test. The total thrombus-formation analysis system (T-TAS) is a microchip-based flow chamber system that mimics physiological conditions and allows for the quantitative analysis of thrombogenicity. The present study investigated the antiplatelet effects of HCQ using T-TAS. METHODS: This was a single-centre cross-sectional study on 57 patients with SLE. We measured the area under the pressure curve for 10 min (PL-AUC10) and the time to 10 kPa (T10) in patients with SLE using T-TAS and examined their relationships with the use of HCQ. PL-AUC10 and platelet aggregation were also measured at several HCQ concentrations using blood samples from healthy donors. RESULTS: PL-AUC10 was significantly lower in the HCQ/real body weight (RBW) ≥5 mg/kg group than in the <5 mg/kg group, while T10 was similar, indicating that HCQ inhibited overall thrombus formation rather than the initiation of thrombus formation. The antiplatelet effects of HCQ were initially detected at HCQ/RBW of approximately 4 mg/kg and reached a plateau at around 5.5 mg/kg. The administration of HCQ/RBW >4.6 mg/kg clearly exerted antiplatelet effects. Additionally, HCQ inhibited thrombus formation in T-TAS and the platelet aggregation response to epinephrine in a dose-dependent manner. CONCLUSIONS: We demonstrated the antiplatelet effects of HCQ under conditions simulating the physiological environment by using T-TAS and identified the range of doses at which HCQ exerted antiplatelet effects.

Long-term transition of antibody titers in healthcare workers following the first to fourth doses of mRNA COVID-19 vaccine: Comparison of two automated SARS-CoV-2 immunoassays.

Anti-spike receptor binding domain (S-RBD) antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which best correlates with virus-neutralizing antibody is useful for estimating the period of protection and identifying the timing of additional booster doses. Long-term transition of the S-RBD antibody titer and the antibody responses among healthy individuals remain unclear. In the present study, therefore, we monitored the S-RBD antibody titers of 16 healthcare workers every 4 weeks for 76 weeks after vaccination with a fourth dose of mRNA-1273 (Moderna) following three doses of BNT162b2 (Pfizer/BioNTech) using two commercial automated immunoassays (Roche and Abbott). Two antibody responses to the vaccine were similar with an up-down change before and after the second (weeks 3), third (weeks 40) and fourth (week 72) vaccinations, but the titer did not fall below the assay's positivity threshold in any individual. The peak level of the geometric mean titer (GMT) in the Roche assay was highest after the third vaccination, and that in Abbott assay was highest after the fourth vaccination but almost equal to that after the third vaccination. Both the geometric mean fold rise (GMFR) demonstrated by the Roche and Abbott assays were highest after the third vaccination. Antibody titers determined by the Roche and Abbott assays showed a positive strong correlation (correlation coefficient: 0.70 to 0.99), but the ratio (Roche/Abbott) of antibodies demonstrated by both assays increased 0.46- to 8.26-fold between weeks 3 and 76. These findings will be helpful for clinicians when interpreting results for SARS-CoV-2 antibody levels and considering future vaccination strategies.

Two-Year Seroprevalence Surveys of SARS-CoV-2 Antibodies among Outpatients and Healthcare Workers in Ehime, Japan.

We conducted two-year seroprevalence surveys of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies among outpatients and healthcare workers (HCWs) at Ehime University Hospital. Data were collected for outpatients and HCWs in June 2020 (1st survey), December 2020 (2nd survey), July 2021 (3rd survey), and December 2021 (4th survey), focusing on demographics, occupation, and the seroprevalence of anti-SARS-CoV-2 antibodies. Blood samples were obtained from randomly selected outpatients who visited our hospital for medical care and HCWs undergoing regular medical checks with opt-out informed consent. SARS-CoV-2 antibody positivity was evaluated using two laboratory-based quantitative tests. The total number of participants enrolled was 6,369 (1st survey: 1,000 outpatients and 743 HCWs, 2nd survey: 1,000 outpatients and 407 HCWs, 3rd survey: 1,000 outpatients and 804 HCWs, 4th survey: 1,000 outpatients and 415 HCWs). The prevalence of SARS-CoV-2 antibodies among outpatients and HCWs was 0-0.1% and 0-0.124% during the research period, respectively, and changed little over time. These findings suggest that the magnitude of COVID-19 infection during the pandemic among outpatients and HCWs in this rural hospital might have been small.

Retroperitoneal Hemorrhage in Patients with COVID-19 Undergoing Hemodialysis: Three Case Reports.

A 73-year-old man receiving hemodialysis and antiplatelets was admitted with a mild case of COVID-19. Heparin was added, and iliopsoas hemorrhage developed. He was successfully treated by interventional radiology. A 76-year-old man receiving hemodialysis and antiplatelets was admitted with mild COVID-19. Heparin was added, and iliacus hemorrhage developed. Despite heparin discontinuation, he died of worsening pneumonia. A 74-year-old man undergoing hemodialysis was admitted with severe COVID-19. Gastrointestinal bleeding developed during continuous hemodiafiltration with heparin. Upon switching to nafamostat and increasing the dose, iliopsoas hemorrhage developed. Despite interventional radiology, he died of infectious complications. Attention to hemorrhagic complications is therefore needed in patients with COVID-19.

A case of clinically amyopathic dermatomyositis that was refractory to intensive immunosuppressive therapy including tofacitinib, but successfully treated with plasma exchange therapy.

Clinically amyopathic dermatomyositis (CADM) patients often develop rapidly progressive interstitial lung disease (RP-ILD). A high level of anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab) before treatment is associated with RP-ILD development, a poor treatment response, and poor survival. The prognosis of CADM patients remains poor due to ILD even with combined intensive immunosuppressive therapy. Recently, several additional therapies, including tofacitinib (TOF) and plasma exchange (PE) therapy, have been reported to be effective. We herein report a case of CADM-ILD with a high level of anti-MDA5 Ab that was refractory to combined intensive immunosuppressive therapy including TOF, but successfully treated with PE. The following are possible reasons why TOF was ineffective: (1) cytokines that were not suppressed by TOF played an important role in RP-ILD; (2) TOF was administered later than previously reported; and (3) TOF did not suppress pathological substances such as antibodies. On the other hand, PE removes cytokines and various pathological substances. Therefore, PE may be a more reasonable additional therapy for intractable CADM-ILD.

Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy. METHODS: The relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study). RESULTS: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months. CONCLUSION: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.

Giant Cell Arteritis Presenting with Ptosis and Diplopia.

Giant cell arteritis (GCA) is vasculitis of large-sized vessels that can lead to vision loss. We herein report a rare case of GCA accompanied by ptosis and diplopia as early symptoms, which were caused by third nerve palsy. A 78-year-old man presented with fever, right temporal headache, right eyelid ptosis, and diplopia. GCA was confirmed by a temporal artery biopsy. The symptoms disappeared after a slight delay following the administration of prednisolone. Unlike vision loss, ptosis and diplopia are considered to be reversible and responsive to treatment. GCA should not be ruled out if patients exhibit these ophthalmic symptoms.

The association between ear involvement and clinical features and prognosis in ANCA-associated vasculitis.

OBJECTIVE: The concept of otitis media with ANCA-associated vasculitis (OMAAV) was recently proposed by the study group of the Japan Otological Society. However, little is known about the effect of ear involvement on the clinical features and prognosis of AAV. We investigate this issue in this study. METHODS: We retrospectively examined 36 patients diagnosed with OMAAV and 44 patients diagnosed with AAV without ear involvement (non-OMAAV) at Ehime University Hospital from 2013 to 2018. We collected serological findings including ANCA type and titer, C-reactive protein (CRP), serum creatinine level, organ involved at initial diagnosis, treatment, remission, disease relapse, and mortality from medical records. We investigated whether clinical features and outcomes differed between the OMAAV and non-OMAAV groups. RESULTS: Age, ANCA titer, and CRP at initial diagnosis were not significantly different between the two groups, and the rate of intravenous cyclophosphamide (IVCY) use also did not differ. The proportions of patients with concurrent eye involvement, facial palsy (FP), and hypertrophic pachymeningitis (HCP) were significantly higher in the OMAAV than in the non-OMAAV group (p = 0.005, 0.005 and 0.049, respectively), while both renal and peripheral nerve involvement were significantly less common in OMAAV patients (p = 0.04). Among the 30 patients with renal involvement, serum creatinine level at diagnosis was significantly lower in the OMAAV group (p = 0.04). The mortality rate was 8.3% in OMAAV and 6.8% in non-OMAAV cases, but this difference was not significant. The rate of relapse was 33.3% in OMAAV and 13.6% in non-OMAAV cases; this difference was significant (p = 0.04). CONCLUSIONS: Serological measurements of disease activity did not differ between the groups. Eye involvement, FP, and HCP, however, were significantly more common in AAV with ear involvement. In addition, renal involvement was less common and renal impairment was milder in AAV with ear involvement. These findings can be considered clinical features. The relapse rate was significantly higher in AAV with ear involvement.

A multicenter non-randomized, uncontrolled single arm trial for evaluation of the efficacy and the safety of the treatment with favipiravir for patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7-14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS.

The hearing prognosis of otitis media with ANCA-associated vasculitis.

OBJECTIVE: The concept of otitis media with ANCA-associated vasculitis (OMAAV) was recently proposed by the study group of the Japan Otological Society. However, information remains limited regarding the hearing outcome of OMAAV. Thus, we investigated this issue in this study. METHODS: We retrospectively examined 50 ears from 32 patients diagnosed with OMAAV at our hospital between 2010 and 2019. We collected the results of pure tone audiometry (PTA) at diagnosis and changes in PTA threshold after treatment, serological findings including ANCA type, titer, soluble interleukin-2 receptor (sIL2R), and C-reactive protein, organs involved at initial diagnosis, treatment, and disease relapse from medical records. According to the hearing outcome, patients were divided into two groups: good prognosis and poor prognosis groups. We investigated the clinical features, treatment, and changes in PTA between the groups. RESULTS: Age, sex, ANCA negativity, and the use of intravenous cyclophosphamide (IVCY) were significantly related to hearing prognosis of OMAAV, while other organs involved at diagnosis, serological findings, and relapse rate were not significantly associated with hearing outcome. Hearing level at diagnosis was significantly better in good prognosis group, while air-bone gap (ABG) was not significantly different between the groups. The air conduction (AC), bone conduction (BC), and ABG were significantly improved in the good prognosis group. However, ABG was not improved in the poor prognosis group, while AC and BC were significantly improved. The AC hearing level at diagnosis (58.5 dB) and hearing gain at 2 weeks after treatment (12.5 dB) were suggested as good indicators for predicting the hearing outcome of OMAAV. CONCLUSION: Younger age, male sex, shorter period from onset to diagnosis, the use of IVCY, and better hearing threshold at diagnosis were the good prognostic factors of the hearing outcome of OMAAV. These results suggest that earlier diagnosis of OMAAV might be needed for better hearing outcome, and the use of IVCY may be recommended for the treatment of OMAAV patients.

Incidence and Antimicrobial Susceptibilities of Mycoplasma hominis in Pregnant Females, Ehime University Hospital.

OBJECTIVE: Mycoplasma hominis usually colonizes the lower urogenital tract and has been occasionally associated with pelvic inflammatory disease, postpartum fever, preterm labor in pregnant females. The aim of this study was to investigate the incidence and antimicrobial susceptibilities of M. hominis isolated from the urogenital tracts of pregnant females. METHODS: Specimens were obtained from the urogenital tract of pregnant females at Department of Obstetrics and Gynecology, Ehime University Hospital, between November 2014 and December 2017. The identification of M. hominis was confirmed by the polymerase chain reaction (PCR) methods. The minimum inhibitory concentrations (MICs) of antibiotics were measured using a broth microdilution assay. RESULTS: Of the 1074 specimens tested, 63 (5.9%) were positive for M. hominis. The M. hominis-positive rate was highest at 21.3% between 18 and 24 years old. The 21 (25.6%) of 82 patients with bacterial vaginosis were positive for M. hominis. The 17 (40.5%) of 42 patients delivered by cesarean section that occurred infections including of intrauterine infection and pelvic abscess were positive for M. hominis. They were all administered ß-lactam antibiotics before and after cesarean section. All patients recovered immediately following administration of clindamycin (CLDM). ß-lactam antibiotics, macrolides and fosfomycin (FOM) were all resistant against M. hominis strains. In contrast, M. hominis strains were susceptible to CLDM, minocycline (MINO) and quinolones. CONCLUSIONS: Our data suggests that the prevalence of genital M. hominis in pregnant females is high at younger age, bacterial vaginosis and infections after cesarean section with ß-lactam antibiotics administration. CLDM, MINO and quinolones may be recommended against M. hominis infection. Especially, CLDM can be used as the adequate agent for pregnant females because tetracycline and quinolones are undesirable during pregnancy and lactation.

Association between daptomycin susceptibility and teicoplanin resistance in Staphylococcus epidermidis.

Staphylococcus epidermidis infections are a common occurrence in hospitals, particularly in catheter-related bloodstream and surgical site infections and infective endocarditis. Higher daptomycin minimum inhibitory concentration (MIC) values may be associated with daptomycin treatment failure among patients with S. epidermidis infections. We therefore conducted a retrospective cohort study to determine the predictive value of daptomycin susceptibility. A retrospective study was undertaken in 1,337 patients with S. epidermidis infections. Data were collected from 1 January 2013 to 31 December 2016 at Ehime University Hospital, and included the following clinicopathological factors for evaluation: age, sex, resistance to vancomycin or teicoplanin, and history of antimicrobial therapy. Multiple analysis was performed using logistic regression to identify factors that independently and significantly affected the daptomycin resistance. Daptomycin-resistant S. epidermidis was identified in 38 (2.8%) patients. According to the multiple analysis, only higher MIC values (≥16 mg/L) for teicoplanin (P < 0.0001) were independently associated with an increased risk of developing daptomycin resistance. In conclusion, higher teicoplanin MIC values may predict resistance to daptomycin treatment in S. epidermidis infections.

The treatment outcomes of rituximab for intractable otitis media with ANCA-associated vasculitis.

OBJECTIVE: To investigate treatment outcomes, hearing outcomes, and adverse effects of rituximab (RTX) for intractable otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV). METHODS: Twenty-three patients who met the criteria proposed by the OMAAV study group were included. RTX was used for patients who had difficulty achieving induction of remission using glucocorticoids (GC) and intravenous cyclophosphamide (IVCY). RESULTS: Six patients were treated with RTX (RTX group), while 17 patients did not require RTX for induction of remission (non-RTX group). All six patients in the RTX group achieved remission. Age, sex, and months from onset to diagnosis did not differ significantly between the groups. The air-conduction hearing thresholds at diagnosis and remission were 71.7±6.3dB and 50.1±5.1dB in the RTX group, and 56.8±4.8dB and 35.8±4.8dB in the non-RTX group, respectively. Hearing level at remission was significantly better in the non-RTX group (p<0.05), while hearing gain did not differ significantly between the groups. Infectious complications were similar between the groups. CONCLUSIONS: Our findings suggest that RTX is effective and safe for intractable OMAAV patients who have a poor response to GC and IVCY.

Intractable Otitis Media Presenting as Falsely Positive for Proteinase 3-ANCA: A Case Report.

Herein, we report a case of otitis media caused by methicillin-resistant Staphylococcus aureus (MRSA), presenting as falsely positive for proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCA). A 47-year-old woman was referred to our hospital with a complaint of left otorrhea. An otorrhea culture yielded MRSA, and the patient was treated using tympanoplasty. Postoperative administration of teicoplanin lead to drug-induced neutropenia and was discontinued 4 days after the operation. One month after the operation, the patient's otorrhea recurred, and it was accompanied by hearing impairment. The otorrhea culture yielded MRSA again, while serum was positive for PR3-ANCA (6.8 U/mL). As MRSA was detected in the patient's otorrhea sample, she was treated with linezolid. Her symptoms then improved immediately. Although the PR3-ANCA positivity remained, the patient's otorrhea and hearing impairment had not recurred for 3 years when this report was submitted. Therefore, we conclude that this is a case of false PR3-ANCA positivity.

Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study). RESULTS: Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers). CONCLUSIONS: We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

Comparison of Localized and Systemic Otitis Media With ANCA-Associated Vasculitis.

OBJECTIVE: To investigate differences in immune activity based on the presence of multiple organ involvement in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and whether hearing outcomes are different between patients with AAV localized to the ear and patients with systemic AAV. STUDY DESIGN: Retrospective case review. SETTING: University hospital. PATIENTS: Twenty patients with otitis media with AAV (OMAAV) who met the criteria proposed by the OMAAV study group in Japan. MAIN OUTCOME MEASURE(S): Serum levels of C-reactive protein, ANCA titer, soluble interleukin-2 receptor levels, and hearing outcome. RESULTS: Thirteen patients had disease involvement of organs other than the ear (systemic OMAAV group); involvement was localized to the ear in seven patients (localized OMAAV group). Serum levels of C-reactive protein, ANCA titer, and soluble interleukin-2 receptor were not significantly different between the groups. Hearing levels at diagnosis and in remission were significantly worse in the localized OMAAV group compared with the systemic OMAAV group. Hearing gain was not significantly different between groups. CONCLUSION: It is suggested that immune activity in patients with AAV localized to the ear is equivalent to activity in patients with systemic AAV. Therefore, we may need treatment for OMAAV equal in intensity to that for systemic AAV. As the hearing level at diagnosis was worse in patients with AAV localized to the ear than in patients with systemic AAV, earlier diagnosis may be needed to improve hearing outcome.

T-cell Receptor Signaling Activates an ITK/NF-κB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy.

Purpose: T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell-specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy.Experimental Design: Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines.Results: Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3 and promotes chemotherapy resistance.Conclusions: These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance. Clin Cancer Res; 23(10); 2506-15. ©2016 AACR.

Human tolerogenic dendritic cells generated with protein kinase C inhibitor are optimal for functional regulatory T cell induction - A comparative study.

Tolerogenic dendritic cells (tDCs) are a promising therapeutic tool for specific induction of immunological tolerance. Human tDCs can be generated ex vivo using various compounds. However, the compound(s) most suitable for clinical application remain undefined. We compared the tolerogenic properties of tDCs treated with protein kinase C inhibitor (PKCI), dexamethasone, vitamin D3 (Vit D3), rapamycin (Rapa), interleukin (IL)-10, transforming growth factor (TGF)-ß, and a combination of peroxisome proliferator-activated receptor γ agonist and retinoic acid. All tDCs had a semi-mature DC phenotype. PKCI-, TGF-ß-, and Rapa-tDCs showed CCR7 expression and migration to CCL19, but other tDCs showed little or none. PKCI- and IL-10-tDCs induced functional regulatory T cells more strongly than other tDCs. The tolerogenic properties of all tDCs were stable against proinflammatory stimuli. Furthermore, PKCI-tDCs were generated from patients with rheumatoid arthritis and primary Sjögren's syndrome. Therefore, PKCI-tDCs showed the characteristics best suited for tolerance-inducing therapy.