To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA).
Of 346 patients who received 24 weeks of double-blind ...treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks.
The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity 28-joint Disease Activity Score (DAS28) ≤ 3.2, or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy.
TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.
Background
Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We ...previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression.
Methods
Since AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions.
Results
DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN.
Conclusion
Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2.
Androgen inhibits cell proliferation and promotes the differentiation of atypical cells in CIN lesions via an ELF3‐dependent pathway partially by attenuating FOXP4 function. This indicates that androgen is a possible therapeutic agent for non‐surgical CIN treatment that inhibits CIN progression by inducing squamous differentiation.
Background and Objectives: It is still unclear whether sarcoidosis is likely to be associated with tumors. In addition, the use of an immune checkpoint inhibitor has been reported to initiate the ...onset of sarcoidosis. We retrospectively analyzed tumor development before and after the diagnosis of sarcoidosis and examined the impact of having a history of tumors on the activity or the severity of sarcoidosis. Materials and Methods: We recruited 312 consecutive cases of sarcoidosis and analyzed the tumor development before and after the onset of sarcoidosis. Results: Among them, 25 cases were diagnosed with malignant tumor after diagnosis of sarcoidosis. In the analysis of the tumor-development group after diagnosis of sarcoidosis, both serum angiotensin I-converting enzyme and mediastinal lymph node size were significantly reduced at the time of malignant tumor diagnosis compared to at the onset of sarcoidosis, indicating that the decreasing activity of sarcoidosis may be partly associated with tumor development. Furthermore, we examined 34 cases having tumor history before the onset of sarcoidosis and analyzed the effect of tumor history on the severity of sarcoidosis. Cases with a malignant tumor in the past were older and had less complicated organs of sarcoidosis than cases without malignant tumors in the past. Oral corticosteroid therapy was administrated more frequently in cases without malignant tumors in the past, indicating that the history of a malignant tumor may influence the severity of sarcoidosis. Conclusion: These results indicate that tumor development may be partly associated with the activity or severity of sarcoidosis.
Hard X-Ray Detector (HXD) on Board Suzaku Takahashi, Tadayuki; Abe, Keiichi; Endo, Manabu ...
Publications of the Astronomical Society of Japan,
01/2007, Letnik:
59, Številka:
sp1
Journal Article
Recenzirano
Odprti dostop
The Hard X-ray Detector (HXD) on board Suzaku covers a wide energy range from 10 keV to 600 keV by the combination of silicon PIN diodes and GSO scintillators. The HXD is designed to achieve an ...extremely low in-orbit background based on a combination of new techniques, including the concept of a well-type active shield counter. With an effective area of
$142 \,\mathrm{cm}^{2}$
at 20 keV and
$273 \,\mathrm{cm}^{2}$
at 150 keV, the background level at sea level reached
$\sim 1 \times 10^{-5} \,\mathrm{cts} \,\mathrm{s}^{-1} \,\mathrm{cm}^{-2} \,\mathrm{keV}^{-1}$
at 30 keV for the PIN diodes, and
$\sim 2 \times 10^{-5} \,\mathrm{cts} \,\mathrm{s}^{-1} \,\mathrm{cm}^{-2} \,\mathrm{keV}^{-1}$
at 100 keV, and
$\sim 7 \times 10^{-6} \,\mathrm{cts} \,\mathrm{s}^{-1} \,\mathrm{cm}^{-2} \,\mathrm{keV}^{-1}$
at 200 keV for the phoswich counter. Tight active shielding of the HXD results in a large array of guard counters surrounding the main detector parts. These anti-coincidence counters, made of
$\sim 4 \,\mathrm{cm}$
thick BGO crystals, have a large effective area for sub-MeV to MeV
$\gamma$
-rays. They work as an excellent
$\gamma$
-ray burst monitor with limited angular resolution (
$\sim 5^{\circ}$
). The on-board signal-processing system and the data transmitted to the ground are also described.
To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission.
...Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2).
A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation.
ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.
Diacylglycerol lipase alpha (DAGLA), which catalyzes the hydrolysis of diacylglycerol to 2-arachidonoylglycerol and free fatty acid, is required for axonal growth during the brain development and for ...retrograde synaptic signaling at mature synapses. So far, no information was found regarding the possible role of DAGLA in human tumorigenesis. Thus, the current study sought to clarify the contribution of DAGLA in oral squamous cell carcinomas (OSCCs) and assess the clinical possibilities for OSCC treatment. Using real-time quantitative reverse transcription-polymerase chain reaction, immunoblotting, and immunohistochemistry, we found a significant up-regulation of DAGLA in OSCCs compared with normal cells and tissues both at mRNA and protein expression levels. Knockdown models in OSCC-derived cell lines for DAGLA (siDAGLA) and treatment with a lipase inhibitor (orlistat) showed several depressed cellular functions, including cellular proliferation and migratory activities through cell-cycle arrest at G1 phase. Furthermore, we found that DAGLA-positive OSCC samples were correlated highly with the primary tumoral size. We concluded that DAGLA may be a key determinant in tumoral progression and might be a therapeutic target for OSCCs.
•DAGLA was up-regulated in human oral squamous cell carcinoma (OSCC) cells compared with human normal oral keratinocytes (HNOKs).•Overexpression of DAGLA in OSCCs controlled cell proliferation through cell-cycle progression.•The tumoral volume of the orlistat-treated group was clearly smaller than that of the control group in vivo.•DAGLA expression level might be a useful diagnostic indicator and a new therapeutic target for OSCCs.
Immune reconstitution inflammatory syndrome (IRIS) is an immune reaction that occurs along with the recovery of the patient's immunity. Tuberculosis-related IRIS (TB-IRIS) upon tumor necrosis factor ...(TNF)-α inhibitor treatment has been reported in non-human immunodeficiency virus (HIV) patients. However, the importance of biological treatment, as a risk factor of IRIS, has not yet been established. In this study, we examined TB-IRIS in non-HIV patients to explore the role of TNF-α inhibitor treatment. Out of 188 patients with pulmonary TB, seven patients had IRIS. We examined univariate logistic and multivariate analysis to elucidate risk factors of TB-IRIS. Univariate analysis indicated that usage of immunosuppressive drugs, TNF-α inhibitors, and history of food or drug allergy were significantly related with TB-IRIS. On initial treatment, the values of serological markers such as serum albumin and serum calcium were significantly related with TB-IRIS. There was a higher mortality rate in patients with TB-IRIS. Furthermore, multivariate analysis revealed that usage of TNF-α inhibitors, history of allergy, and serum hypercalcemia were related to TB-IRIS. Usage of TNF-α inhibitors, history of allergy, and serum hypercalcemia may be independent predictors of TB-IRIS in non-HIV patients. Since higher mortality has been reported for TB-IRIS, we should pay attention to TB patients with these risk factors.
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