The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). Beneficial effects are limited by mechanisms of chemoresistance, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. The organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and decreased expression in HCC has been associated with poorer response. METHODS: The multicenter retrospective TRANSFER study involved tumor biopsies from 39 patients with advanced HCC and sorafenib therapy for ≥4 wk. Endpoint was the relationship between clinicopathological features and immunohistological result. Immunostaining was performed using specific primary anti-OCT1-head and anti-OCT1-tail antibodies. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, taking into account the localization of the staining at the plasma membrane as positive or negative. RESULTS: Results confirmed OCT1 downregulation in half of the cases investigated (10% absent, 38% weak). However, only one third of tumors expressing OCT1 displayed plasma membrane location (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different sorafenib response was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found (Log Rank p<0.001). No association between OCT1 expression at the plasma membrane with tumor stage, previous treatment with TACE or radiological response was seen.In conclusion, these results indicate that the presence of OCT1 at the plasma membrane, rather than its expression levels, is related to better outcome of HCC patients treated with sorafenib.

Effectiveness and acceptance of acupuncture in patients with chronic low back pain: results of a prospective, randomized, controlled trial.

OBJECTIVE: To investigate the effectiveness of additional acupuncture in patients with chronic low back pain participating in an inpatient rehabilitation program. DESIGN: Patients were randomly assigned to one of two groups (A and B), both receiving a standard rehabilitation program according to German guidelines. Patients in group A additionally underwent acupuncture twice weekly, conducted by two Chinese physicians with education in Traditional Chinese Medicine (TCM). At the beginning and end of the program, as well as at 3 months after, patients completed questionnaires about health-related quality of life (Short-Form 36 Health Survey [SF-36]), sociodemographic and clinical data, attitude towards TCM, pain, and adverse events. SETTING: Inpatient rehabilitation clinic in Germany. PATIENTS: Patients with chronic low back pain participating in an inpatient rehabilitation program. OUTCOME MEASURES: Acceptance of acupuncture, health-related quality of life, and pain/symptoms. RESULTS: One hundred and forty-three patients were analyzed: 74 in group A (intervention) and 69 in group B (controls); 67% were men and 33% were women, with a mean age of 50.7 years. Acceptance of TCM was excellent: 89% of the patients would want TCM to be integrated into standard inpatient rehabilitation, and 83% would even have paid for TCM if necessary. Responses to SF-36 questionnaires showed that group A reported significantly better physical functioning, general health, vitality, and emotional role than group B. Pain outcomes in group A were superior to those in group B. Specifically, pain with sitting/standing, pain upon carrying loads of 10 kg or more, and prickling in hands and feet were significantly diminished. CONCLUSION: Acupuncture was highly accepted and had positive effects in patients with chronic low back pain. These results show that acupuncture can be an effective, well-tolerated therapy with no major adverse events.

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice.

Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages--as was found to occur in human chronic venous leg ulcers and the mouse model--induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16(INK4a)-dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.