Mechanism of alcohol consumption-mediated Th2-polarized immune response

Alcohol consumption impairs Th1-mediated cellular immune responses and enhances serum IgE levels. It has been reported that the elevated IgE levels are associated with a Th2 polarization response, but the mechanisms for enhancing Th2 polarization by the ethanol treatment remain to be elucidated. The aim of this review is to present and discuss the mechanism of Th2 polarization response by alcohol. IL-12 production by APCs such as monocytes, macrophages, and dendritic cells (DCs) preferentially leads to Th1 polarization. Acute ethanol consumption results in a significant decrease in IL-12 production in LPS-stimulated DCs and a CD40/CD40L interaction between CD40 on the DCs and CD40 ligand expressed on activated T cells. This suggests that Th2 polarization by ethanol is caused by impaired IL-12 production from APCs. In contrast, the induction of IL-10 by LPS is enhanced by ethanol treatment, suggesting that elevated IL-10 may play a role in ethanol-induced suppression of IL-12. However, ethanol inhibited IL-12 production in LPS-stimulated DCs devoid of IL-10 (IL-10/DC), suggesting that down-regulation of IL-12 by ethanol is independent of the IL-10 levels. Furthermore, several studies report that PGE2, cAMP and linolic acid, and endogenous lipid mediators released in inflammatory conditions, also inhibit IL-12 production. These inhibitory effects are similar to the IL-12 inhibition by ethanol. In addition, increase in the levels of these lipid mediators is induced by ethanol treatment. Alternatively, cytokine signaling studies indicate that IL-12 production by DCs is negatively regulated by PI3K and GSK-3, but positively regulated by p38 MAPK, mTOR, and NF-kappa B. Thus, it seems possible that ethanol may interact on the upstream of IL-12 producing a signal pathway. In fact, ethanol alters the stability of cell membrane, and suppresses clustering of TLR4 and recruitment of signaling molecules into lipid rafts, where it associates with the Ser/Thr kinase and the adaptor proteins, and forms a signaling complex. Down-regulation of lipid raft signaling is results in the impaired IL-12 production leading to the Th1 polarization, and causes CD4+ T cells to differentiation toward the Th2 lineage.     

A new peptide motif present in the protective antigen of anthrax toxin exerts its efficiency on the cellular uptake of liposomes and applications for a dual-ligand system

Protective antigen (PA) is a nontoxic protein present in anthrax toxin. Domain 4 of PA (PA-D4) acts as a receptor binding site for tumor endothelial marker 8 (TEM8). In this study, KYND motif from PA-D4 was utilized as a ligand against TEM8. The efficiency of KYND motif on cellular association was assessed by evaluating the cellular uptake of PEGylated liposomes (PEG-LPs) in TEM8 positive and negative cells. The peptide was attached on the top of the PEG of PEG-LP. Compared to PEG-LP, KYND modified PEG-LP (KYND-PEG-LP) enhanced the cellular uptake to a greater extent in all cell lines. Based on the inhibition assay, no receptor involvement was observed in the cellular association of KYND-PEG-LP, suggesting that KYND motif functions as a cell penetrating peptide (CPP) which facilitated the internalization of PEG-LP via clathrin mediated endocytosis pathway. Further enhancement of cellular uptake was observed when KYND-PEG-LP was combined with octaarginine (R8) on the surface of lipid membrane as dual-CPP ligand formulation, however, when PEG-LP combined with only R8, only negligible enhancement was observed. These findings suggest that two CPP ligands act in a synergistic fashion; therefore the dual-CPP ligand based liposomal formulation can be assumed to be an effective delivery system.     

A patient with obstructive jaundice due to bleeding in the common bile duct after ultrasound-guided liver biopsy

A-63-year-old man was referred to our hospital for interferon therapy to treat chronic hepatitis C. The patient complained of right upper abdominal pain 1 hour after the ultrasound-guided liver biopsy. Bleeding in the gallbladder and the common bile duct were found on emergency CT. Obstructive jaundice due to the common bile duct hematoma was diagnosed, and endoscopic retrograde cholangiopancreatography(ERCP) was performed, and a filling defect thought to be a hematoma was seen in the bile duct on cholangiography. The hematoma in the bile duct was extracted after endoscopic sphincteroyomy.     

A case of gastric cancer with abdominal wall invasion treated by weekly low-dose paclitaxel therapy

Here we report a case of gastric cancer with diffuse abdominal wall invasion treated with weekly low-dose paclitaxel therapy. A 62-year-old male visited our hospital because of abdominal distention, prepubic tumor,and testicular hydrocele. Computed tomography revealed diffuse swelling of the abdominal wall and hydronephrosis of the right kidney. Upper gastrointestinal endoscopy demonstrated type 3' advanced gastric cancer. Pathological diagnosis of both gastric tumor and abdominal wall biopsy specimens was poorly-differentiated adenocarcinoma containing signet ring cell carcinoma. Low-dose paclitaxel (90 mg/body) was given once a week for 3 weeks. Abdominal wall swelling like cuirass disappeared after 2 courses of low-dose paclitaxel therapy. Nine repeated courses of this regimen have been given until now; the relapse of the abdominal wall invasion has not become apparent, and primary gastric lesion has been a stable disease. Diffuse abdominal wall invasion of gastric cancer like cuirass without ascites is a rare condition, and low-dose paclitaxel was very effective for this condition.     

Treatment outcome in older patients with childhood acute myeloid leukemia

BACKGROUND.

Older age has historically been an adverse prognostic factor in pediatric acute myeloid leukemia (AML). To the authors' knowledge, the impact of age relative to that of other prognostic factors on the outcome of patients treated in recent trials is unknown.

METHODS.

Clinical outcome and causes of treatment failure of 351 patients enrolled on 3 consecutive protocols for childhood AML between 1991 and 2008 were analyzed according to age and protocol.

RESULTS.

The more recent protocol (AML02) produced improved outcomes for patients aged 10 years to 21 years compared with 2 earlier studies (AML91 and AML97), with 3‐year rates of event‐free survival (EFS), overall survival (OS), and cumulative incidence of refractory leukemia or recurrence (CIR) for this group being similar to those of patients aged birth to 9 years: EFS: 58.3% ± 5.4% versus 66.6% ± 4.9% (P = .20); OS: 68.9% ± 5.1% versus 75.1% ± 4.5% (P = .36); and CIR: 21.9% ± 4.4% versus 25.3% ± 4.2% (P = .59). The EFS and OS estimates for patients aged 10 to 15 years overlapped those for patients aged 16 to 21 years. However, the cumulative incidence of toxic death was significantly higher for patients aged 10 to 21 years compared with younger patients (13.2% ± 3.6% vs 4.5% ± 2.0%; P = .028).

CONCLUSIONS.

The survival rate for older children with AML has improved on the results of a recent trial and is now similar to that of younger patients. However, deaths from toxicity remain a significant problem for patients in the older age group. Future trials should focus on improving supportive care while striving to develop more effective antileukemic therapy. Cancer 2012. © 2012 American Cancer Society.     

Superselective intra-arterial chemoradiotherapy with docetaxel-nedaplatin for advanced oral cancer

Cisplatin-based, superselective, intra-arterial chemotherapy concurrent with radiotherapy (SSIACRT) has gained wide acceptance as a common/curative treatment for advanced head and neck cancer. We combined nedaplatin (CDGP) with docetaxel (DOC) as a new combination in SSIACRT for advanced oral squamous cell carcinoma in 2003. Twenty-two patients with advanced oral cancer were treated by radiotherapy (66 Gy) concurrent with superselective intra-arterial DOC (40 mg/body) and CDGP (80 mg/m2) infusion between 2003 and 2009. Complete response was achieved in 18 (81.8%) of the 22 patients. Of the 17 patients with positive neck disease, 16 (94%) were assessed as disease-free. The 5-year overall survival rate was 78.5%, and the major adverse effects were leukocytopenia and mucositis. Five patients (22.7%) developed distant metastases post-treatment. These results indicate that intra-arterial docetaxel-nedaplatin infusion concurrent with radiotherapy is efficacious for advanced oral cancer. The side effects are easily manageable, and the most important outcome of the treatment is the preservation of patients' quality of life (QOL) and improved prognosis.     

Protein kinase A inhibition facilitates the antitumor activity of xanthohumol,a valosin‐containing protein inhibitor

Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin‐containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.     

A case of high CEA colon cancer responding to neoadjuvant chemotherapy with FOLFIRI

We report a case of high CEA advanced colon cancer, which we were able to down stage after treatment with FOLFIRI-1. The patient was a 56-year-old woman who had advanced sigmoid colon cancer with high CEA. It was suspected that the tumor had directly invaded the ovary by CT scan. For curative operation, hysterectomy was considered necessary. Neoadjuvant therapy was performed to avoid an extensive operation. After the fourth course, according to colonoscopy and CT findings, a significant tumor reduction was obtained. Sigmoid colorectomy with D3 nodal dissection was then performed. The histological diagnosis was pT1, pN0, PStage I. The histological effect was observed in lymph node metastasis. The patient was recurrence free at her 3-year follow-up examination.     

Tiotropium bromide as add-on therapy to inhaled corticosteroids for treating asthma

Introduction: Bronchial asthma is becoming increasingly prevalent worldwide. Although first-line therapy with inhaled corticosteroids (ICS) with or without long-acting β2 agonists (LABA) has significantly improved the clinical outcomes of asthma, they cannot provide all asthmatics with good control and thus alternatives or add-on drugs are required. Tiotropium is a long-acting muscarinic antagonist that has been used to treat chronic obstructive pulmonary disease and it has been approved for treating asthma in some countries. This agent has similar bronchodilatory effects to those of LABA and might also have anti-inflammatory and anti-remodeling effects.

Areas covered: Some pivotal clinical trials have found tiotropium effective as an add-on medication for low-to-medium doses of ICS for treating symptomatic asthma and asthma that remains uncontrolled despite ICS plus LABA therapy.

Expert opinion: Whether or not tiotropium has anti-inflammatory and anti-remodeling effects in humans with asthma is an important issue. Predictors that would identify patients who would derive the maximal potential benefit from treatment with tiotropium in addition to their current therapy are also needed. Although the cardiovascular toxicity of tiotropium is less remarkable in asthma than in chronic obstructive pulmonary disease, longer and larger studies are still needed to confirm the safety of tiotropium for treating asthma.     

Neuroimaging-Aided Prediction of the Effect of Methylphenidate in Children with Attention-Deficit Hyperactivity Disorder: A Randomized Controlled Trial

Although methylphenidate hydrochloride (MPH) is a first-line treatment for children with attention-deficit hyperactivity disorder (ADHD), the non-response rate is 30%. Our aim was to develop a supplementary neuroimaging biomarker for predicting the clinical effect of continuous MPH administration by using near-infrared spectroscopy (NIRS). After baseline assessment, we performed a double-blind, placebo-controlled, crossover trial with a single dose of MPH, followed by a prospective 4-to-8-week open trial with continuous MPH administration, and an ancillary 1-year follow-up. Twenty-two drug-naïve and eight previously treated children with ADHD (NAÏVE and NON-NAÏVE) were compared with 20 healthy controls (HCs) who underwent multiple NIRS measurements without intervention. We tested whether NIRS signals at the baseline assessment or ΔNIRS (single dose of MPH minus baseline assessment) predict the Clinical Global Impressions-Severity (CGI-S) score after 4-to-8-week or 1-year MPH administration. The secondary outcomes were the effect of MPH on NIRS signals after single-dose, 4-to-8-week, and 1-year administration. ΔNIRS significantly predicted CGI-S after 4-to-8-week MPH administration. The leave-one-out classification algorithm had 81% accuracy using the NIRS signal. ΔNIRS also significantly predicted CGI-S scores after 1 year of MPH administration. For secondary analyses, NAÏVE exhibited significantly lower prefrontal activation than HCs at the baseline assessment, whereas NON-NAÏVE and HCs showed similar activation. A single dose of MPH significantly increased activation compared with the placebo in NAÏVE. After 4-to-8-week administration, and even after MPH washout following 1-year administration, NAÏVE demonstrated normalized prefrontal activation. Supplementary NIRS measurements may serve as an objective biomarker for clinical decisions and monitoring concerning continuous MPH treatment in children with ADHD.