Treatment of depigmented skin is an unmet medical need.
Melanocytes or stem cells thereof residing in the outer root sheath (ORS) of hair follicles might be used to repigment skin.
After ...de-epidermisation, autologous ORS cell solutions were applied to 5 patients with vitiligo and 1 with leucoderma.
Stable repigmentation in a variable percentage was documented in all the patients.
Applying ORS-derived melanocytes is a promising technology to improve autologous melanocyte transplantation.
To describe disease characteristics and treatment modalities in a multidisciplinary cohort of systemic lupus erythematosus (SLE) patients in Switzerland.
Cross-sectional analysis of 255 patients ...included in the Swiss SLE Cohort and coming from centres specialised in Clinical Immunology, Internal Medicine, Nephrology and Rheumatology. Clinical data were collected with a standardised form. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), an integer physician's global assessment score (PGA) ranging from 0 (inactive) to 3 (very active disease) and the erythrocyte sedimentation rate (ESR). The relationship between SLE treatment and activity was assessed by propensity score methods using a mixed-effect logistic regression with a random effect on the contributing centre.
Of the 255 patients, 82% were women and 82% were of European ancestry. The mean age at enrolment was 44.8 years and the median SLE duration was 5.2 years. Patients from Rheumatology had a significantly later disease onset. Renal disease was reported in 44% of patients. PGA showed active disease in 49% of patients, median SLEDAI was 4 and median ESR was 14 millimetre/first hour. Prescription rates of anti-malarial drugs ranged from 3% by nephrologists to 76% by rheumatologists. Patients regularly using anti-malarial drugs had significantly lower SELENA-SLEDAI scores and ESR values.
In our cohort, patients in Rheumatology had a significantly later SLE onset than those in Nephrology. Anti-malarial drugs were mostly prescribed by rheumatologists and internists and less frequently by nephrologists, and appeared to be associated with less active SLE.
Bullous pemphigoid, the most common autoimmune subepidermal bullous disorder, is associated with autoantibodies targeting antigenic sites clustered within the extracellular domain of BP180. To ...investigate epitope and subclass specificity of autoantibodies in bullous pemphigoid, we developed an enzyme-linked immunosorbent assay utilizing baculovirus-expressed recombinant forms of the NH2- and COOH-terminal regions of the extracellular domain of BP180 and examined sera obtained from patients with active bullous pemphigoid (n=116) and controls (n=100). Ninety-three (80%) and 54 (47%) of the 116 bullous pemphigoid sera recognized the NH2- and COOH-terminal regions, respectively, of the extracellular domain of BP180. Detailed analysis demonstrates that (i) this novel enzyme-linked immunosorbent assay is highly specific (98%) and sensitive (93%) as 108 of 116 bullous pemphigoid sera reacted with at least one of the baculovirus-derived recombinants, (ii) in active bullous pemphigoid, autoantibodies against the NH2-terminus of the extracellular domain of BP180 were predominantly of the IgG1 class, whereas a dual IgG1 and IgG4 response to this region was related to a more severe skin involvement, (iii) autoreactivity against both the NH2- and COOH-terminal regions was more frequently detected in patients with mucosal lesions, and (iv) levels of IgG (and IgG1) against the NH2-terminal, but not against the COOH-terminal portion of the extracellular domain of BP180, reflected disease severity indicating that autoantibodies against the NH2-terminus are critical in the pathogenesis of bullous pemphigoid. In conclusion, this novel enzyme-linked immunosorbent assay represents a highly sensitive and specific assay for rapid diagnosis of bullous pemphigoid and related disorders and may provide predictive parameters for the management of bullous pemphigoid patients.
Lessons Learned
Local tolerance of intralesional treatment of melanoma skin metastases with BQ788 is excellent.
Hints of efficacy are observed, consisting of both direct effects (decreased expression ...of endothelin receptor B EDNRB and of survival factors, reduced proliferation) and indirect effects (enhanced immune cell infiltration and angiogenesis).
Patients in future trials should be screened for EDNRB expression level prior to treatment because only patients with high EDNRB‐expressing melanomas (four of five) responded to BQ788.
Future studies should be performed for at least 2 weeks because reduced lesion growth was observed in the only patient that was treated for longer than 1 week.
Background.
This first‐in‐human proof‐of‐concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.
Methods.
Three patients received a single intralesional BQ788 application of 3 mg. After 3–7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0–3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate‐buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.
Results.
No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788‐ and PBS‐treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788‐treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.
Conclusion.
The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.
经验
• 病灶内注射 BQ788 治疗黑色素瘤皮肤转移的耐受性非常好。
• 观察到了有效性的迹象, 包括直接效应 内皮素受体 B (EDNRB) 和存活因子的表达下调, 增殖减少 和间接效应 (免疫细胞浸润及血管生成增加)。
• 将来的临床试验应在开始前对患者 EDNRB 表达水平进行筛查, 因为只有 EDNRB 高表达的黑色素瘤患者 (4/5 例) 对 BQ788 有治疗反应。
• 将来的研究应该至少持续 2 周, 因为我们只在治疗超过 1 周的患者中观察到病灶生长抑制。
摘要
背景. 本研究为首次应用于人体的概念验证研究, 旨在检验肿瘤内注射内皮素受体 B (EDNRB) 拮抗剂 BQ788 的安全性及其临床前结果在人类黑色素瘤患者中是否具有重现性。
方法. 3 例患者接受单次肿瘤内注射 BQ788 3 mg。3 ∼ 7 天后对病灶进行测量和切除以进行分析。第 4 例患者的给药剂量上调至累积剂量 8 mg (4×2.0 mg, 0 ∼ 3天, 在第 4 天切除病灶), 第 5 例患者上调至 10 mg(3×3.3 mg, 0、3、 10 天, 14 天后切除病灶)。同时使用磷酸盐缓冲液 (PBS) 治疗对照病灶。所有标本均在研究者不知晓临床结果的情况下进行处理和分析。
结果. 由于患者数少 (n = 5) 以及给药模式的变异性, 我们无法进行统计学评价。我们在所有给药剂量水平均未观察到不良事件。所有观察结果均与临床前研究获得的结果相一致。相应地, 在 BQ788 和 PBS 处理标本中未观察到肿瘤坏死的程度存在差异。此外, 患者 2 和 5 的 EDNRB 和 Ki67 表达下调, 而患者 1 的下调幅度较小。与此相似, 患者 2 和 5 的 EDNRB mRNA 表达下调, 患者 2 、 3 和 5 的 BCL2A1 和/或 PARP3 表达下调。CD31 和 CD3 免疫组化结果的半定量评分分别提示, 接受 BQ788 治疗的患者 2 和 4 分别出现血管和淋巴细胞增加, 这一点非常重要。同时, 我们在所有患者中均观察到 EDNRB 和 HIF1A 表达水平呈负相关。最后, 我们通过测量病灶发现患者 5 (唯一 1 例治疗超过 1 周的患者) 病灶生长受到抑制。
结论. 病灶内注射 BQ788 耐受良好, 且直接和间接迹象均提示治疗减少了黑色素瘤细胞的存活力。The Oncologist 2015;20:1121–1122
Although numerous chemokines act on monocytes, none of them is specific for these cells. Here, we show that breast and kidney-expressed chemokine (BRAK) is a highly selective monocyte ...chemoattractant. Migration efficacy and Bordetella pertussis toxin-sensitive Ca(2+) mobilization responses to BRAK were strongly enhanced after treatment of monocytes with the cyclic AMP-elevating agents prostaglandin E(2) and forskolin. BRAK is the first monocyte-selective chemokine, as other types of blood leukocytes or monocyte-derived dendritic cells and macrophages did not respond. Expression in normal skin keratinocytes and dermal fibroblasts as well as lamina propria cells in normal intestinal tissues suggests a homeostatic rather than an inflammatory function for this chemokine. In addition, macrophages were frequently found to colocalize with BRAK-producing fibroblasts. We propose that BRAK is involved in the generation of tissue macrophages by recruiting extravasated precursors to fibroblasts, which are known to secrete essential cytokines for macrophage development.
Multiuser Turbo Decoding in Narrowband Systems Hunziker, Thomas
2020 23rd International Symposium on Wireless Personal Multimedia Communications (WPMC),
2020-Oct.-19
Conference Proceeding
With the Internet of Things taking shape, interference becomes a major issue especially in the sub-GHz bands destined for long range, low power data transfer. Since many power limited devices do not ...afford sophisticated collision avoidance measures, packet collisions may result in severe performance degradation. We analyze a multiuser decoder intended to let a central station deal with temporally overlapping packets from distributed transmitters. Assuming a state-of-the-art turbo encoding of the information, the multiuser decoder is derived from a factor graph extended to model the temporal packet overlapping. We show that the resulting iterative decoding procedure is capable to jointly decode coinciding packets at error rates close to those of single user decoders.
Bullous pemphigoid is a subepidermal blistering disease associated with auto-antibodies (auto-ab) to BP180 and BP230. We developed ELISAs utilizing baculovirus-encoded recombinant proteins of BP230 ...and BP180 and studied their diagnostic and prognostic values by assessing the profile of the auto-ab response in 127 patients with BP. 39 patients had focal involvement, whereas 88 had generalized disease; 51 individuals served as controls. The results indicate: (1) BP180 IgG reactivity was associated with an overall sensitivity of 0.953 and specificity of 0.940; (2) 105 of 127 BP patients also displayed BP230 auto-reactivity, the global diagnostic performance of which, however, was moderate compared to BP180-auto-reactivity (sensitivity 0.815 vs 0.953, specificity 0.648 vs 0.940); (3) 101 patients (79.5%) had concordant BP180 and BP230 reactivity; (4) the association between the presence of BP230 auto-reactivity and focal involvement was stronger than in generalized disease (odds ratio (OR) 17.7 vs 10.2), independently from BP180 auto-ab profile; (5) correlation of total IgG with IgG1 and IgG4 was variable for both BP180 and BP230. Collectively, the global diagnostic properties of the BP180-ELISA outperform those of the BP230-ELISA. Presence of BP230 auto-reactivity, however, supports the diagnosis of BP and might be indicative for the extent of the disease.
The outer root sheath of hair follicles plays an important role in epidermal regeneration in vivo. Keratinocytes isolated by explantation of outer root sheath tissue have extensive proliferative ...capacity irrespective of donor age, which probably depends on pluripotent epithelial stem cells residing in the outer root sheath. These keratinocytes can be organotypically grown to epidermal equivalents in vitro. We report here that in a multicenter, randomized phase II study, EpiDex™, a tissue‐engineered, fully differentiated autologous epidermal equivalent derived from keratinocytes of the outer root sheath of plucked anagen hair follicles, is as effective as split‐thickness skin autografting in the promotion of healing and complete closure of recalcitrant vascular leg ulcers. (WOUND REP REG 2003;11:248–252)
Intravenously applied normal human immunoglobulin G (IgG) has anti-inflammatory effects in the treatment of autoimmune diseases. Systemic inflammation can originate from an overreacting amplification ...loop of the complement system. In blood, C3b2-containing complexes maintain complement amplification much better than the extremely short-lived C3b. Therefore, in patients with the complement-dependent autoimmune disease, dermatomyositis, we studied whether intravenously applied normal human IgG (IVIG) stimulated in vivo inactivation of these complexes. In the course of IVIG treatment, clinically effective in 6 of 8 patients, the concentration of C3b2-containing complexes dropped to 37% ± 14% (n = 6) of the pretreatment level when having infused 0.5 g IgG/kg body weight, increased marginally and in parallel to factor Bb thereafter until full-dose IgG was infused. By day 14 following infusion of 2 g IgG/kg body weight the concentration of C3b2-containing complexes was 66% ± 19%. The plasma concentration of C3 remained constant in myopathic or increased by 15% to 20% in amyopathic patients. In contrast to this, IVIG infusion was associated with consumption of up to 40% of plasma C4 at day 1 to 2 after completion of IVIG infusion. Thus, IVIG had an immediate and long-lasting attenuating effect on complement amplification in vivo, despite the fact that it induced classical complement pathway activation.
Approximately 20% of leg ulcers remain unresponsive to the best conservative standard of care. So far, these patients could either receive conventional skin grafts or had to accept their intractable ...wound. Skin substitutes from cell culture may represent a promising alternative to heal a major part of these patients on a non-surgical, potentially more cost-effective basis.
To systematically evaluate the first 68 patients treated in Switzerland (Swiss EpiDex® field trial 2004-2008).
Retrospective study on EpiDex treatment of a complete consecutive series of 68 patients with chronic wounds (66 chronic leg ulcers, 2 sores) unresponsive to best conservative standard of care. The primary end point was complete wound closure within 9 months after transplantation, the secondary end points change of wound surface area, pain reduction and overall judgement by the patient. Adverse effects were infection, dermatitis and others. Calculation of treatment costs was made.
By the end of the study, 50/68 (74%) of patients had their wound completely healed venous 29/37 (78%); mixed 7/9 (78%); others 14/22 (64%); 10/68 (15%) had the wound surface area reduced by >50%, and 8/68 (12%) did not respond to the EpiDex treatment. Wound pain disappeared completely in 78% and partially in 13%. Fifteen patients (22%) received antibiotics for wound infection, and 2 (3%) developed dermatitis (not related to the local therapy). Average treatment costs for venous ulcers amounted to EUR 5,357, compared to EUR 5,722-8,622 reimbursed according to the German DRG system (2010) for an in-patient skin graft.
EpiDex may effectively heal up to three quarters of recalcitrant chronic leg ulcers. Thus, it represents an intermediate step to avoid costly in-patient split-skin mesh graft treatments. Patients remain mobilized, and a donor site is avoided. Large wound size or a necrotic wound bed limit the use of EpiDex. Otherwise, it offers the opportunity to avoid conventional skin grafts in a significant number of chronic leg ulcer patients.
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