Clinically, patients' adherence to biologic treatment is not only related to efficacy but also to adverse events, cost and other factors. To evaluate long-term viability of biologic treatment, both the percentage of and reasons for discontinuation of treatment were investigated. In this study, patients treated with infliximab (n = 38), adalimumab (n = 59) and ustekinumab (n = 30) were included and observed for 12 months. Clinical efficacy was evaluated using a 75% reduction of Psoriasis Area and Severity Index score (PASI-75), and patients who discontinued treatment were considered as not having achieved PASI-75. In addition, drug survival rate (DSR) was investigated. In patients treated with infliximab, PASI-75 was 68.4% and DSR was 73.3% by the end of treatment. In patients treated with adalimumab, PASI-75 was 50.8% and DSR was 79.7%. In patients treated with ustekinumab, PASI-75 was 63.3% and DSR was 96.7%. Several patients discontinued treatment because of insufficient efficacy due to secondary failure in infliximab or primary failure in adalimumab. To increase treatment efficacy, it will be necessary for these patients to use an additional concomitant treatment. Higher efficacy is expected with biologics than with conventional treatments; however, the actual clinical efficacy over a long period of time may be insufficient if they are used without any concomitant treatments.
Regulation of transcription elongation by RNA polymerase II (Pol II) is a key regulatory step in gene transcription. Recently, the little elongation complex (LEC)—which contains the transcription elongation factor ELL/EAF—was found to be required for the transcription of Pol II-dependent small nuclear RNA (snRNA) genes. Here, we show that the human Mediator subunit MED26 plays a role in the recruitment of LEC to a subset of snRNA genes through direct interaction of EAF and the N-terminal domain (NTD) of MED26. Loss of MED26 in cells decreases the occupancy of LEC at a subset of snRNA genes and results in a reduction in their transcription. Our results suggest that the MED26 NTD functions as a molecular switch in the exchange of TBP-associated factor 7 (TAF7) for LEC in order to facilitate the transition from initiation to elongation during transcription of a subset of snRNA genes.
The ratio of the elderly among psoriasis patients has been increasing. However, satisfactory long-term management of psoriasis for the elderly is challenging because of the more frequent presence of comorbidities, and the higher risk of adverse events from systemic therapeutic agents than younger patients. The use of ustekinumab (UST) appears to be an appropriate systemic treatment because it is considered less likely to cause adverse events than other systemic treatments, as well as necessitating fewer hospital visits. Our retrospective study aimed to evaluate the efficacy and safety profile of UST in elderly patients with psoriasis. The study included 24 patients aged over 65 years (range, 65-88 years; mean, 73.1 years) with moderate to severe plaque psoriasis with impaired quality of life. Efficacy and safety were assessed over a 1-year period using the Psoriasis Area and Severity Index (PASI) and the Dermatology Live Quality Index (DLQI). The efficacy was evaluated by the proportion of subjects who achieved ≥75% reduction in PASI score (PASI 75). PASI 75 responses were 56.5% at week 16, 59.1% at week 28, and 60.0% at week 52. None of the patients developed any serious infection during the 1-year treatment. The mean DLQI score at weeks 0, 16, 28, and 52 was 7.8 ± 6.0, 2.5 ± 3.4, 1.4 ± 1.7, and 1.2 ± 1.7, respectively. UST showed sufficient efficacy for elderly patients with psoriasis without any serious infection over the 1-year treatment. Our results suggest that UST is the preferable agent for the treatment of elderly patients with psoriasis.
The interaction of programmed death-1 (PD-1) with its ligand, programmed death ligand-1 (PD-L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD-1 (sPD-1) than those with limited cutaneous SSc and healthy individuals. Serum sPD-1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD-L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD-L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD-1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD-1/PD-L1 interaction may contribute to the development of skin sclerosis in SSc.
The number of elderly patients with psoriasis is increasing in Japan. However, biologic treatment is generally considered to be challenging in elderly patients, due to their increased risk of complications compared with younger patients. Our retrospective study aimed to evaluate the safety profile and efficacy of biologics in senior elderly patients (≥75 years old) with psoriasis. The study involved a cohort of 27 patients aged 75-88 years who were being treated with biologics over a period of more than 1 year. Initial biologics administrated to were adalimumab (five cases) and ustekinumab (22 cases). Eight patients discontinued treatment: two developed cancer; one was transferred to hospital; and five others experienced either bone fracture, interstitial pneumonia, cerebral hemorrhage resulting in death, decrepitude or developed hepatopathy following prophylactic tuberculosis treatment. Efficacy, evaluated by the percentage of patients achieving 75% reduction of Psoriasis Area and Severity Index score, was 76.9% at week 16 (n = 26), 88.0% at week 24 (n = 25) and 90.5% at week 52 (n = 21). Biologic treatments thus show clear efficacy in elderly patients with psoriasis, however, the increased frequency of adverse events requires rigorous patient observation.
Glioma stem cells (GSCs) have the capacity to repopulate tumors and mediate resistance to radiotherapy and chemotherapy. The Notch signaling pathway is important in proliferation, stem cell maintenance, cell differentiation, and tumorigenesis in GSCs. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. In vitro study, the γ-secretase inhibitor inhibited NICD, Hes1 and pVEGFR2 expressions in GSCs. GSCs cultured under endothelial conditions undergo endothelial differentiation. Tumor samples were collected from 27 patients at the time of tumor recurrence. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with I Notch-1 positivity (6.8 months). We noted that GSCs have the potential for endothelial differentiation with Notch activity. We believe that Notch-1 is a potential target and/or biomarker for antiangiogenic treatments.
not receive adequate counseling from physicians. A survey of American households found the majority of adults who received a vaccination during the 2009e2010 influenza season reported that health care providers were the most influential information source regarding the flu vaccine (Maurer et al., 2010), suggesting dermatologists can potentially be an important resource for psoriasis patients. For younger psoriasis patients, a dermatologist may be the only health care provider they see regularly, making it important for dermatologist to provide counseling about recommended vaccinations. While this is a large, population-based study examining influenza vaccination rates in patients with psoriasis, there are some limitations to the use of administrative claims data to study vaccination rates, including misclassification and lack of generalizability to patients with other types of insurance or without insurance. Further research on understanding why adults with psoriasis do not receive recommended vaccinations will help to create targeted interventions to improve vaccination rates and decrease hospitalizations in adults with psoriasis. ORCID Megan H. Noe: http://orcid.org/0000-0001-8481-4711 CONFLICTS OF INTEREST Joel M. Gelfand served as a consultant for BMS, Boehringer Ingelheim, GSK, Janssen Biologics, Novartis Corp, UCB (DSMB), and Pfizer, receiving honoraria; and receives research grants (to the Trustees of the University of Pennsylvania) from AbbVie, Janssen, Novartis Corp, Celgene, Ortho Dermatologics, and Pfizer; and received payment for continuing medical education work related to psoriasis that was supported indirectly by Lilly and Ortho Dermatologics.
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