Substrate switchable Suzuki–Miyaura coupling for benzyl ester vs. benzyl halide

Two reaction conditions were developed to accomplish the substrate switchable Suzuki–Miyaura coupling of benzyl derivatives and arylboronic acid derivatives. Under conditions for esters, benzyl esters such as carbonates and acetates reacted with arylboronic acids to afford the corresponding diarylmethanes. However, the benzyl halides did not react under the same conditions. On the other hand, benzyl halides such as bromides and chlorides furnished diarylmethanes under conditions for halides, under which benzyl ester substrates did not react, in which water was found to play an important role. This switching system was tested using the intermolecular/intramolecular competitive reactions, during which the desired products could be synthesized by selecting the appropriate reaction conditions.

Two reaction conditions were developed to accomplish the substrate switchable (benzyl esters vs. benzyl halides) Suzuki–Miyaura coupling.     

Inflammation and prostate carcinogenesis

Quite a few epidemiological studies including meta‐analyses indicate that prostate inflammation is associated with increased risk of prostate cancer. The cause of inflammation in the prostate is speculated to be several microorganisms that cause prostatitis or sexually transmitted infections. Other specific microorganisms, such as xenotropic murine leukemia virus‐related virus, are also reported to relate to the development of prostate cancer; however, the contribution of this microorganism to prostate cancer development needs to be carefully interpreted. Environmental factors, especially dietary factors, might also be associated with prostate cancer development. Among related dietary factors, charred meat carcinogen 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine might be a link between environmental factors and inflammation, because 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine has the potential to accelerate prostate inflammation through its estrogenic effect. In light of these findings, preventing or reducing prostate inflammation might be one strategy for chemoprevention of prostate cancer.     

Effects of propiverine hydrochloride, an anticholinergic agent, on urethral continence mechanisms and plasma catecholamine concentration in rats

Introduction and hypothesis

Anticholinergics are used to treat overactive bladder. Anticholinergic agents such as propiverine hydrochloride reportedly increase plasma catecholamine levels in rats. It is also known that active urethral closure mechanisms prevents stress urinary incontinence (SUI), which is enhanced by central and peripheral noradrenergic system activation. Therefore, we examined the influence of propiverine hydrochloride on urethral anti-incontinence function in rats.

Methods

Adult female rats were divided into propiverine and vehicle-treated groups. The propiverine group was given propiverine orally once a day for 2 weeks, after which urethral function and plasma concentrations of catecholamine (dopamine, norepinephrine, epinephrine) were tested.

Results

Urethral baseline pressure measured by a microtransducer-tipped urethral catheter and leak-point pressure during passive intravesical pressure elevation were significantly increased in the propiverine group compared with the vehicle group. Plasma norepinephrine and epinephrine levels in the propiverine group were also significantly increased.

Conclusions

Propiverine treatment that increases plasma catecholamine levels could contribute to improvement of SUI conditions by increasing urethral resistance.     

The F‐prostaglandin receptor is a novel marker for tumor endothelial cells in renal cell carcinoma

Tumor angiogenesis is necessary for tumor progression and metastasis; therefore, tumor blood vessels are potential therapeutic targets in anticancer therapy. We previously reported that tumor endothelial cells (TECs) exhibit different phenotypes compared with normal endothelial cells (NECs), and microarray analyses of mouse TECs and NECs have shown that several genes are upregulated in TECs compared with NECs. Among these genes, the expression levels of prostaglandin F receptor (PTGFR) mRNA, which encodes the prostaglandin F receptor (FP), were higher in TECs than in NECs. It has been reported that FP and its ligand, prostaglandin F_2α, are involved in tumor angiogenesis. However, there have been no reports of the expression of PTGFR in the tumor vessels of renal cell carcinoma (RCC). Thus, we isolated human TECs (hTECs) from RCCs. The expression levels of PTGFR mRNA were also upregulated in hTECs. In addition, immunostaining showed that the PTGFR was expressed in human tumor blood vessels in vivo. These findings suggested that PTGFR is a novel TEC marker and that it may be a novel target for antiangiogenic therapy for RCC.     

Long-term administration of PPI reduces treatment failures after esophageal variceal band ligation: a randomized, controlled trial

Background and purpose

Elective esophageal variceal ligation (EVL) is performed to decrease the risk of variceal hemorrhage. EVL is associated with adverse effects, including post-ligated bleeding, chest pain, and dysphagia. Proton pump inhibitors (PPIs) are the most potent pharmacological agents for inhibition of gastric acid secretion. However, the long-term effect of PPIs after EVL remains unclear. The aim of this study was to assess the efficacy of rabeprazole, a PPI, after variceal eradication by EVL.

Methods

We performed a randomized, controlled trial in Kitasato University East Hospital. The primary endpoint was treatment failure, defined as variceal hemorrhage or severe medical complications. Between July 2007 and September 2010, 43 patients were randomized into this study and followed up until September 2010.

Results

Twenty-one patients in the rabeprazole arm received 10?mg rabeprazole daily after EVL, and 22 patients in the control received no antisecretory treatment from the same stage. Baseline characteristics did not differ between the groups (median Child-Pugh score, 6; median age, 62?years; median follow-up, 18.7?months). The trial was stopped early after an interim analysis showed that the risk of bleeding and failure of rabeprazole treatment was lower than that of no antisecretory treatment with the log-rank test showing a significant difference between the groups (P?=?0.007) and a hazard ratio of 0.098 [95% confidence interval, 0.012?C0.79 (P?=?0.029)].

Conclusions

Long-term administration of PPIs reduced the risk of treatment failure after EVL. Acid suppression therapy should also be considered as a treatment option after EVL.     

Portal hemodynamic effects of sorafenib in patients with advanced hepatocellular carcinoma: a prospective cohort study

Background and aims

Sorafenib is currently in clinical use as an oral multikinase inhibitor that blocks tumor growth and cell proliferation in advanced hepatocellular carcinoma (HCC). It has been demonstrated in a translating study that sorafenib had a beneficial effect on portocollateral circulation in cirrhotic animals with portal hypertension. This study was prospectively performed to evaluate the portal hemodynamic effect of sorafenib in patients with advanced HCC using duplex Doppler ultrasonography (DDU).

Methods

Twenty-five Child-Pugh class-A patients with advanced HCC had received sorafenib at a dose of 400?mg twice daily. Primary outcomes were changes in portal venous area (PVA; cm²) as seen by using DDU before and after a 2-week administration of sorafenib. Secondary outcomes included the changes of laboratory data and other flow data revealed on DDU.

Results

PVA was significantly decreased after a 2-week administration (0.78?±?0.23 vs. 0.64?±?0.25, P?=?0.023), while the portal venous flow velocity (PVV; cm/s) was not significantly changed (0.22?±?0.06 vs. 0.24?±?0.07, P?=?0.17). Therefore, the congestion index (PVA/PVV), which reflects the pathophysiological hemodynamics of portal venous system, was significantly decreased (3.9?±?1.7 vs. 3.0?±?1.4, P?=?0.042).

Conclusions

We demonstrated the portal hemodynamic effect of sorafenib in patients with advanced HCC. Considering that this was a short-term study, because sorafenib could be a potential beneficial therapeutic agent for portal hypertension, it will be necessary to verify its clinical benefits for portal hypertension in future studies.     

Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus

Objective. Although hepatitis B virus (HBV) DNA can be detected in liver or sera of patients without serum hepatitis B surface antigen (HBsAg), its clinical relevance in hepatocarcinogenesis remains controversial. This observational cohort study was conducted to clarify the risk factors, including the presence of serum HBV DNA and hepatitis B core antibody (anti-HBc), for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). Material and methods. The study comprised 123 patients with LC due to HCV, and negative for HBsAg. The risk factors for HCC development were analyzed by univariate and multivariate analysis. Serum samples were assayed for HBV DNA using real-time polymerase chain reaction. Results. Serum HBV DNA was detectable in 14 patients (11.4%) and serum anti-HBc in 96 (78.0%). During the follow-up period (mean 53.3 months), 80 patients (65.0%) developed HCC. The cumulative HCC development rate was significantly higher in the anti-HBc-positive group than in the anti-HBc-negative group (p=0.0039), but did not differ between the serum HBV DNA-positive and -negative groups (p=0.8570). The multivariate analysis indicated that male gender, alpha-fetoprotein (AFP) 20 ng/ml or greater, average serum alanine aminotransferase (ALAT) 80 IU/l or greater and the presence of anti-HBc were independent risk factors for development of HCC (p=0.038, p=0.013, p=0.020 and p=0.001, respectively). Conclusions. Serum anti-HBc, which indicates a previous HBV infection, has clinical significance in hepatocarcinogenesis in patients with HCV-related LC, but serum HBV DNA does not. Therefore, anti-HBc in serum is a significant predictor for HCC.     

Monotherapeutic high-dose-rate brachytherapy for prostate cancer: A dose reduction trial

Purpose

To report preliminary results of our second regimen with 45.5 Gy/7 fractions aiming to reduce toxicity, compared with our first regimen with 54 Gy/9 fractions, using high-dose-rate (HDR) brachytherapy as monotherapy for prostate cancer.

Materials and methods

From 2005 through 2010, 63 patients with localized prostate cancer were treated with HDR brachytherapy alone in 45.5 Gy/7 fractions for 4 days. Thirty-four patients were considered as intermediate-risk and 29 as high-risk. Thirty-seven patients also received neoadjuvant and/or adjuvant hormonal therapy. Biologically effective dose assuming α/β = 1.5 Gy (BED_1.5) was reduced from 270 Gy to 243 Gy, and BED_3.0 from 162 Gy to 144 Gy, compared to previous 54 Gy/9 fractions for 5 days.

Results

Median follow-up time was 42 months (range 13–72). Grade 2 acute toxicities occurred in six (9.5%), late toxicities in five (7.9%) patients, and Grade 3 or higher in none. Grade 2 late gastrointestinal toxicity rate was 1.6%, compared with 7.1% for the 54 Gy regimen. Three-year PSA failure-free rates for intermediate- and high-risk patients were 96% and 90%, which were comparable to 93% and 85% for the 54 Gy regimen.

Conclusions

Compared to the 54 Gy/9 fractions regimen, dose-reduced regimen of 45.5 Gy/7 fractions using HDR brachytherapy as monotherapy preliminarily showed an equivalent or lower incidence rate for acute and late toxicities without compromising the excellent PSA failure-free rate. Further studies with more patients and longer follow-up are warranted.