Mechanochemical Synthesis of PdO2 Nanoparticles Immobilized over Silica Gel for Catalytic Suzuki-Miyaura Cross-Coupling Reactions Leading to the C-3 Modification of 1H-Indazole with Phenylboronic Acids.

The C-3 modification of 1H-indazole has produced active pharmaceuticals for the treatment of cancer and HIV. But, so far, this transformation has seemed less available, due to the lack of efficient C-C bond formation at the less reactive C-3 position. In this work, a series of silica gel-supported PdO2 nanoparticles of 25-66 nm size were prepared by ball milling silica gel with divalent palladium precursors, and then employed as catalysts for the Suzuki-Miyaura cross-coupling of 1H-indazole derivative with phenylboronic acid. All the synthesized catalysts showed much higher cross-coupling yields than their palladium precursors, and could also be reused three times without losing high activity and selectivity in a toluene/water/ethanol mixed solvent. Although the palladium precursors showed an order of activity of PdCl2(dppf, 1,1'-bis(diphenylphosphino)ferrocene) > PdCl2(dtbpf, 1,1'-bis(di-tert-butylphosphino)ferrocene) > Pd(OAc, acetate)2, the synthesized catalysts showed an order of C1 (from Pd(OAc)2) > C3 (from PdCl2(dtbpf)) > C2 (from PdCl2(dppf)), which conformed to the orders of BET (Brunauer-Emmett-Teller) surface areas and acidities of these catalysts. Notably, the most inexpensive Pd(OAc)2 can be used as a palladium precursor for the synthesis of the best catalyst through simple ball milling. This work provides a highly active and inexpensive series of catalysts for C-3 modification of 1H-indazole, which are significant for the large-scale production of 1H-indazole-based pharmaceuticals.

Induction of antitumor immunity in mice by the combination of nanoparticle-based photothermolysis and anti-PD-1 checkpoint inhibition.

Generation of durable tumor-specific immune response without isolation and expansion of dendritic cells or T cells ex vivo remains a challenge. In this study, we investigated the impact of nanoparticle-mediated photothermolysis in combination with checkpoint inhibition on the induction of systemic antitumor immunity. Photothermolysis based on near-infrared light-absorbing copper sulfide nanoparticles and 15-ns laser pulses combined with the immune checkpoint inhibitor anti-PD-1 antibody (αPD-1) increased tumor infiltration by antigen-presenting cells and CD8-positive T lymphocytes in the B16-OVA mouse model. Moreover, combined photothermolysis, polymeric conjugate of the Toll-like receptor 9 agonist CpG, and αPD-1 significantly prolonged mouse survival after re-inoculation of tumor cells at a distant site compared to individual treatments alone in the poorly immunogenic syngeneic ID8-ip1-Luc ovarian tumor model. Thus, photothermolysis is a promising interventional technique that synergizes with Toll-like receptor 9 agonists and immune checkpoint inhibitors to enhance the abscopal effect in tumors.

Clinical application of diffusion-weighted magnetic resonance imaging in radiotherapy for nasopharyngeal carcinoma.

OBJECTIVE: To explore the clinical application of diffusion-weighted magnetic resonance imaging (DWI) in nasopharyngeal carcinoma (NPC) diagnosis, detection of lymph node metastasis, radiotherapy and prognosis. METHODS: Twenty patients with diagnosed NPC in an early stage of radiotherapy were enrolled in our department between May 2010 and May 2013. T1 and T2 weighted magnetic resonance imaging and DWI of the nasopharynx and neck were performed 1 week before radiotherapy, during radiotherapy at a dose of 60 Gy, and 1 month after radiotherapy. Pertinent measurements and related data were recorded. RESULTS: In comparison with that before radiotherapy, the ADC value of the nasopharyngeal primary lesion increased significantly during radiotherapy at a dose of 60 Gy and at 1 month after radiotherapy (F = 187.160, P = 0.000). When the dose of radiotherapy reached 60 Gy, the DWI signals from both the neck and the retropharyngeal lymph nodes were significantly lower than those before radiotherapy. CONCLUSION: DWI can be used for sensitive and accurate diagnosis of lymph node metastasis in the neck and retropharyngeal space, monitoring of the radiotherapy effect in early stages of NPC and development of new medical treatment strategies.

Short-Term Outcome of Patients with Cirrhosis and Concurrent Portal Cavernoma Presenting with Acute Variceal Bleeding.

Background and Aim: The outcome of cirrhotic patients with main portal vein occlusion and portal cavernoma after the first episode of acute variceal bleeding (AVB) is unknown. We compared short-term outcomes after AVB in cirrhotic patients with and without portal cavernoma. Methods: Between January 2009 and September 2014, 28 patients with cirrhosis and portal cavernoma presenting with the first occurrence of AVB and 56 age-, sex-, and Child-Pugh score-matched cirrhotic patients without portal cavernoma were included. The primary endpoints were 5-day treatment failure and 6-week mortality. Results: The 5-day treatment failure rate was higher in the cavernoma group than in the control group (32.1% versus 12.5%; p = 0.031). The 6-week mortality rate did not differ between the cavernoma and control group (25% versus 12.5%, p = 0.137). Multivariable Cox proportional hazard regression analyses revealed that 5-day treatment failure (HR = 1.223, 95% CI = 1.082 to 1.384; p = 0.001) independently predicted 6-week mortality. Conclusions: Cirrhotic patients with AVB and portal cavernoma have worse short-term prognosis than patients without portal cavernoma. The 5-day treatment failure was an independent risk factor for 6-week mortality in patients with cirrhosis and portal cavernoma.

MicroPET/CT Imaging of AXL Downregulation by HSP90 Inhibition in Triple-Negative Breast Cancer.

AXL receptor tyrosine kinase is overexpressed in a number of solid tumor types including triple-negative breast cancer (TNBC). AXL is considered an important regulator of epithelial-to-mesenchymal transition (EMT) and a potential therapeutic target for TNBC. In this work, we used microPET/CT with 64Cu-labeled anti-human AXL antibody (64Cu-anti-hAXL) to noninvasively interrogate the degradation of AXL in vivo in response to 17-allylamino-17-demethoxygeldanamycin (17-AAG), a potent inhibitor of HSP90. 17-AAG treatment caused significant decline in AXL expression in orthotopic TNBC MDA-MB-231 tumors, inhibited EMT, and delayed tumor growth in vivo, resulting in significant reduction in tumor uptake of 64Cu-anti-hAXL as clearly visualized by microPET/CT. Our data indicate that 64Cu-anti-hAXL can be useful for monitoring anti-AXL therapies and for assessing inhibition of HSP90 molecular chaperone using AXL as a molecular surrogate.

Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers.

Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.

Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation-Chemoembolization Therapy in Rats.

Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P < .03) and 24 hours (P < .01). Mean ± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63 ± 3.09 and 1.68 ± 0.77 in the CA4P-treated group and 1.29 ± 2.40 and 0.14 ± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm3 ± 1.01, 3.96 cm3 ± 1.75, and 6.13 cm3 ± 2.27 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P < .05). Conclusion CA4P pretreatment caused a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the efficacy of anti-HCC treatment with PTA-CET in rats. © RSNA, 2016 Online supplemental material is available for this article.

[Clinical Characteristics of Wilson's Disease: a Retrospective Analysis of Admission Data among 126 Patients].

OBJECTIVE: To investigate the clinical features of Wilson's disease (WD) for the purpose of avoiding misdiagnosis and therefore improving the prognosis of this rare disease. METHODS: This study enrolled all the patients diagnosed as WD who were admitted to West China Hospital, Sichuan University from Jan 2008 to Dec 2014. Their clinical manifestations, head and abdominal images data were extracted and analyzed. RESULTS: There were a total of 126 patients of WD, male female ratio was 75 : 51, median age was 21-years old. 10.3% (13/126) of them had family history, 87.3% (109/126) patients presented with neuropsychiatric symptoms, 14.3% (18/126) patients manifested as chronic liver disease. All patients had decreased serum ceruloplasmin level < 200 mg/L, 121 (96.9%) patients had serum ceruloplasmin level < 100 mg/L. Magnetic resonance imaging and abdominal ultrasound detected structural abnormalities in 92.7% (102/110) and 88.9% (97/109) patients respectively. Kayser-Fleischer rings on slit-lamp ophthalmologic examination was found in 98.3% (115/117) patients. One patient underwent liver biopsy and the result of rhodanine stain was positive. The time from onset to diagnosis varied from 3 d to 19 years [(1.59 ± 2.66) years]. 20 (15.9%) patients were initially misdiagnosed. CONCLUSION: The patients presenting with neurological signs or unexplained liver disease should be assessed carefully for WD. Serum ceruloplasmin, 24-h urinary copper, Kayser-Fleischer rings and sometimes even liver biopsy could be helpful for the diagnosis.

[Diagnostic value of CT for head and neck pilomatricoma].

OBJECTIVE: To evaluate the CT and pathological features of head and neck pilomatricoma. METHODS: We retrospectively analyzed the CT findings of 13 patients with head and neck pilomatricoma which were pathologically confirmed. Of them 7 patients received plain CT, 2 patients received contrast-enhancement, and 4 patients received plain CT plus contrast-enhancement. RESULTS: All the patients presented with solitary tumors, 9 of them occurred in the parotid gland region, one in the left occipital, one in the right forehead, one in the right parietal, and another one in the left eyelid. The maximal diameter of the tumors ranged from 0.6 to 2.3 cm with a mean of 1.5 cm. All lesions were well-circumscribed, with partial attachment to the overlying skin. Most of lesions were isodense relative to adjacent skeletal muscle on non-enhanced CT scans, sand-like or nodular calcifications within the masses were showed in 8 cases, and no cystic degeneration was found. On contrast-enhanced imaging, mild to moderate homogenous enhancement was showed in 3 cases, heterogeneous moderate enhancement with patchy nonenhancing necrosis area in one case, marked enhancement in one case, and complete calcification with no enhancement in one case. CONCLUSION: Head and neck pilomatricoma presents with certain characteristics on CT, which are useful in the clinical diagnosis and differential diagnosis.

Value of diffusion-weighted magnetic resonance imaging on the follow-up of nasopharyngeal carcinoma after radiotherapy.

PURPOSE: To explore the value of diffusion-weighted imaging (DWI) and magnetic resonance imaging (MRI) on the follow-up of nasopharyngeal carcinoma (NPC) after radiotherapy. MATERIAL AND METHODS: Eighty-three NPC patients after radiotherapy were divided into two groups: 4 cases of residual tumor and 33 cases of non-residual within 6 months, the cases of recurrent and non-recurrent were 5 and 41 over 6 months, respectively. MRI and DWI imaging of these cases were closely analyzed, and the apparent diffusion coefficient (ADC) of the nasopharyngeal residual mass and nasopharyngeal wall thickening, skull base destruction and lateral pterygoid muscle were measured. RESULTS: The ADC of the lateral pterygoid muscle was (1.501 ± 0.069) × 10^{ - 3} mm^{2}/s in 83 cases. The ADCs of the non-residual group, residual group, non-recurrent group and recurrent group were (1.843 ± 0.133.4) × 10^{ - 3} mm^{2}/s, (1.097 ± 0.183) × 10^{ - 3} mm^{2}/s, (1.884 ± 0.134) × 10^{ - 3} mm^{2}/s and (0.787 ± 0.067) × 10^{ - 3} mm^{2}/s respectively.The ADCs of the residual group and recurrent group were lower than that of the lateral pterygoid muscle, while the ADCs of the non-residual group and non-recurrent group were higher than that of the lateral pterygoid muscle.The differences were statistically significant (P < 0.05). CONCLUSION: DWI can provide qualitative and quantitative information about the tumor cellular level; it can also identify residual, local fibrosis and recurrence after NPC radiotherapy sensitively and accurately by measuring the ADC of the region of interest.

Correlation between CT attenuation value and iodine concentration in vitro: discrepancy between gemstone spectral imaging on single-source dual-energy CT and traditional polychromatic X-ray imaging.

INTRODUCTION: To assess the relation between CT attenuation value and iodine concentration in vitro, using gemstone spectral imaging (GSI) with single-source dual-energy CT and traditional polychromatic X-ray imaging (TPXI), respectively. METHODS: A polypropylene phantom with eight test tubes in which iodine concentrations of solution were 0.4, 0.7, 2, 5, 10, 20, 30 and 50 mg/mL underwent GSI and traditional polychromatic X-ray scans (80, 100, 120 and 140 kV(p)), using single-source dual-energy spectral CT (Discovery CT750HD; GE Healthcare Technologies, Milwaukee, WI, USA) at the same tube speed of 0.8 s/rotation. All spectral imaging data were analysed with GSI viewer to obtain monochromatic images (50-140 keV, interval of 10 keV). Computed tomography attenuation values of iodine solution were measured with the same size of regions of interest and at the exact same level for both monochromatic and polychromatic images. The relation between CT attenuation value and iodine concentration was examined. RESULTS: A linear correlation was found between CT attenuation value and iodine concentration for both monochromatic and polychromatic images. Moreover, the fitting coefficients for CT attenuation values and iodine concentrations were closer to one with GSI (r(2) = 0.99824-0.99996) than that with TPXI (r(2) = 0.99640-0.99736). CONCLUSIONS: Owing to the better correlation coefficients between CT attenuation value and iodine concentration, GSI may be a preferred method for quantitative measurement compared with TPXI.

Impact of different window settings on colon polyp measurements with CT virtual colonoscopy: a phantom study.

The aim of this study was to evaluate the impact of window settings on measurement of colon polyps with CT virtual colonoscopy with experiment. Twenty-four artificial polyps' diameter were measured and scanned 10 times with identical scan parameters using a 64-multidetector computed tomographic scanner. The diameter of each polyp was measured using lung window and abdominal soft tissue window settings and compared with the actual diameter. The lung window setting offers accurate measurement of colon polyps.

CT virtual colonoscopy in displaying excavated colon lesions.

The aim of this study was to evaluate the relative values of 2D plane view and 3D intracavity view of CT virtual colonoscopy in displaying colon excavated lesions. Cleaned porcine colon with ulcerative lesion was scanned with multidetector CT. The data were reconstructed and reviewed using 2D plane view and 3D volume-rendered images on a GE AW4.2 workstation. The 3D volume-rendered images showed superiority in displaying excavated lesions.