Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence

Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short‐term, their use is often limited by concerns over long‐term toxicity, including end‐organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF)α receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNFα. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long‐term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted.     

Human chorionic gonadotrophin-beta gene sequences in women with disorders of HCG production

Women with recurrent abortion, primary unexplained infertility, and gestational trophoblastic neoplasia (GTN) manifest disordered human chorionic gonadotrophin (HCG) secretion. Mutations in the HCG beta/luteinizing hormone (LH) beta gene complex could cause aberrant HCG production in these disorders. The purpose of this study was to determine whether HCG beta gene deletions occur in women with recurrent abortion or primary unexplained infertility, and whether HCG beta gene duplications are present in women with GTN. DNA was extracted from 10 patients with unexplained recurrent abortion, 10 patients with unexplained primary infertility, 12 patients with GTN, three partners of women with GTN, and 30 controls. Southern blots were constructed and hybridized with DNA probes for HCG beta-5 and the LH beta gene. No gene deletions were identified in patients with recurrent abortion or primary unexplained infertility. Likewise, no gene duplications were identified in women with GTN. A previously described Mbol restriction fragment length polymorphism (RFLP) was identified in both patients and controls. A new Pstl RFLP was also characterized, but was present in patients and controls. Deletion/duplication mutations in the HCG beta/LH beta gene complex do not appear to be common causes of aberrant HCG production in humans with these disorders.      

抗癌及癌化学预防药物的研究：3α酮醛香豆素衍生物的合成及其抗致突活性与结构间的关系

α酮醛及其衍生物在抗病毒、抗肿瘤方面有一定活性。我们合成了１８个新的３α酮醛香豆素衍生物，研究该类化合物的质谱裂解方式与氢核磁共振谱的特征峰。体外药理筛选发现其中部分化合物有不同程度的抗致突活性，对其构效关系进行了分析，并提出了这类化合物产生抗致突活性的可能亚结构     

The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status

Background

Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition.

Methods

With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII).

Results

Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32% survival advantage in treated mice.

Conclusions

To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.     

Relationships between wasting and linear growth in stunted children

Height-for-age and weight-for-height are commonly used indicators of nutritional status; however, their precise interrelationship remains unclear. We examined the relationship between weight-for-height and linear growth in 127 stunted Jamaican children aged 9-24 months. The children were measured every 6 months over a 2-year period. The initial weight-for-height status was positively associated with linear growth in the following 6-month interval. The change in weight-for-height in the preceding interval was a better predictor of linear growth in the next interval than attained weight-for-height at the beginning of the interval. The results suggest that variations in weight-for-height may influence the rate of linear growth.     

Treatment effects in Trichuris dysentery syndrome

Heavy infection with the geohelminth Trichuris trichiura causes the Trichuris dysentery syndrome (TDS). Growth retardation and anaemia are characteristic of TDS and both are associated with poor development. We have examined the growth and developmental responses to treatment in 19 children aged 27–84 months with TDS. Developmental levels (DQ) were measured with the Griffiths mental development scales. Compared with a control group matched for age, gender and neighbourhood, the TDS children initially had serious deficits in DQ (24 points, p < 0.001). After a year of anthelmintic treatment, the TDS children showed improvement in locomotor development (p < 0.001) compared with the controls. The TDS children also had initial deficits in height-for-age, weight-for-height, mid-upper arm circumference and haemoglobin levels. They caught up rapidly in indices of wasting (weight-for-height and mid-upper arm circumference) and showed steady improvement in height-for-age and haemoglobin levels. Catch-up in height was comparable to that of children recovering from coeliac disease. The importance of continuing prevention after initial treatment is highlighted.     

Chemorepellent axon guidance molecules in spinal cord injury

Regenerating axons stop growing when they reach the border of the glial-fibrotic scar, presumably because they encounter a potent molecular barrier inhibiting growth cone advance. Chemorepulsive axon guidance molecules provide a non-permissive environment restricting and channeling axon growth in the developing nervous system. These molecules could also act as growth-inhibitory molecules in the regenerating nervous system. The receptors for repulsive guidance cues are expressed in the mature nervous system, suggesting that adult neurons are sensitive to the activity of developmentally active repulsive proteins. In this review, we summarize recent observations on semaphorins, ephrins, and slits in the injured brain and spinal cord, providing evidence that these proteins are major players in inhibiting axonal regeneration and establishing the glial-fibrotic scar.