pH Sensing Properties of Flexible,Bias‐Free Graphene Microelectrodes in Complex Fluids: From Phosphate Buffer Solution to Human Serum

Advances in techniques for monitoring pH in complex fluids can have a significant impact on analytical and biomedical applications. This study develops flexible graphene microelectrodes (GEs) for rapid (<5 s), very‐low‐power (femtowatt) detection of the pH of complex biofluids by measuring real‐time Faradaic charge transfer between the GE and a solution at zero electrical bias. For an idealized sample of phosphate buffer solution (PBS), the Faradaic current is varied monotonically and systematically with the pH, with a resolution of ≈0.2 pH unit. The current–pH dependence is well described by a hybrid analytical–computational model, where the electric double layer derives from an intrinsic, pH‐independent (positive) charge associated with the graphene–water interface and ionizable (negative) charged groups. For ferritin solution, the relative Faradaic current, defined as the difference between the measured current response and a baseline response due to PBS, shows a strong signal associated with ferritin disassembly and the release of ferric ions at pH ≈2.0. For samples of human serum, the Faradaic current shows a reproducible rapid (<20 s) response to pH. By combining the Faradaic current and real‐time current variation, the methodology is potentially suitable for use to detect tumor‐induced changes in extracellular pH.     

Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer—Current Treatment Options and Future Perspectives

Gastrointestinal (GI) cancer constitutes a highly lethal entity among malignancies in the last decades and is still a major challenge for cancer therapeutic options. Despite the current combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, the survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence tumor progression and the development of optimal therapeutic strategies for GI malignancies are urgently needed. Currently, the development and the assessment of the efficacy of immunotherapeutic agents in GI cancer are in the spotlight of several clinical trials. Thus, several new modalities and combinational treatments with other anti-neoplastic agents have been identified and evaluated for their efficiency in cancer management, including immune checkpoint inhibitors, adoptive cell transfer, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, and/or combinations thereof. Understanding the interrelation among the tumor microenvironment, cancer progression, and immune resistance is pivotal for the optimal therapeutic management of all gastrointestinal solid tumors. This review will shed light on the recent advances and future directions of immunotherapy for malignant tumors of the GI system.     

Modeling Lung Carcinoids with Zebrafish Tumor Xenograft

Lung carcinoids are neuroendocrine tumors that comprise well-differentiated typical (TCs) and atypical carcinoids (ACs). Preclinical models are indispensable for cancer drug screening since current therapies for advanced carcinoids are not curative. We aimed to develop a novel in vivo model of lung carcinoids based on the xenograft of lung TC (NCI-H835, UMC-11, and NCI-H727) and AC (NCI-H720) cell lines and patient-derived cell cultures in Tg(fli1a:EGFP)^y1 zebrafish embryos. We exploited this platform to test the anti-tumor activity of sulfatinib. The tumorigenic potential of TC and AC implanted cells was evaluated by the quantification of tumor-induced angiogenesis and tumor cell migration as early as 24 h post-injection (hpi). The characterization of tumor-induced angiogenesis was performed in vivo and in real time, coupling the tumor xenograft with selective plane illumination microscopy on implanted zebrafish embryos. TC-implanted cells displayed a higher pro-angiogenic potential compared to AC cells, which inversely showed a relevant migratory behavior within 48 hpi. Sulfatinib inhibited tumor-induced angiogenesis, without affecting tumor cell spread in both TC and AC implanted embryos. In conclusion, zebrafish embryos implanted with TC and AC cells faithfully recapitulate the tumor behavior of human lung carcinoids and appear to be a promising platform for drug screening.     

甲状腺及乳腺多原发癌临床及超声特征

目的 　分析甲状腺及乳腺多原发癌的临床和超声特征。方法 　回顾性分析1990年1月至2013年3月在北京协和医院接受诊治且手术病理证实的甲状腺及乳腺多原发癌24例，比较这些患者的甲状腺癌及乳腺癌临床和超声特征。结果 　24例患者中9例（37.5%）以甲状腺癌首发，其中2例（22.2%）在1年内出现乳腺癌；15例（62.5%）以乳腺癌首发，其中6例（40.0%）在1年内出现甲状腺癌。甲状腺癌和乳腺癌超声表现均多为实性（86.4%和84.2%）、形态不规则（63.6%和94.7%）、纵横比大于1（50.0%和57.9%）、边界不清（63.6%和78.9%）、低回声或极低回声（90.9%和100%）、点状钙化（50.0%和47.4%）、局部丰富血流（50.0%和68.4%）。结论 　甲状腺及乳腺多原发癌的临床和超声特征与单发甲状腺癌及乳腺癌人群相近，超声可有效地筛查甲状腺及乳腺多原发癌，尤其在首发乳腺癌后1年内。     

Brown tumors in dialyzed patients with secondary hyperparathyroidism: Report of 16 cases

Brown tumors (BTs) are relatively uncommon but they are serious complications of renal osteodystrophy. The objective of this study was to analyze the clinical, biological, and radiological characteristics of 16 patients with BTs provoked by secondary hyperparathyroidism (sHPT) and its response to the decrease in parathyroid hormone levels after parathyroidectomy (PTX). The management of that uncommon condition was also reviewed. We conducted a retrospective study including 16 end‐stage renal disease patients who underwent subtotal PTX between 1997 and 2007 for severe sHPT with BTs. Our study included 10 men and 6 women, whose average age was 34 years. All patients were on dialysis. Ten of them were on dialysis for more than 5 years. The median duration on dialysis was 84 months. Patients included suffered from swellings associated with functional limitations. BTs had multiple locations in 7 patients. Jaw was the most frequent location (62%). Radiography and tomodensitometry demonstrated a mixed radio lucent and radio‐opaque lesions with an expansion of the cortical bone. Bone scan demonstrated an increased uptake of lesions. Chirurgical treatment was indicated in all cases because of severe refractory sHPT with functional limitations and/or disfiguring deformities. In all cases, BTs stopped its progression and even decreased in size. However, it was insufficient in four cases, which required a surgical resection. PTX remains an efficacious approach in resistant cases of sHPT with persistent BTs.     

小肠神经内分泌肿瘤24例临床分析

目的 探讨小肠神经内分泌肿瘤（NETs）的临床特点、治疗方法及预后.方法 对24例小肠神经内分泌肿瘤患者的临床资料进行回顾性分析.结果 分期情况：T1期7例、T2期4例、T3期4例、T4期6例,另3例无法确定.分级情况：G1级10例,G2级7例,NEC 5例,MANEC 2例.免疫组织化学：Syn、CgA、NSE阳性表达率分别为95%、79%、75%.临床表现：上腹疼痛17例,溃疡出血2例,胆系扩张、梗阻性黄疸、瘙痒5例,恶心呕吐、贫血等3例,类癌综合征1例,无症状1例.治疗：18例十二指肠NETs患者中内镜下切除6例,全身姑息化疗1例,胰十二指肠切除11例,其中术后辅助化疗6例;6例空回肠NETs患者中手术切除3例,肝转移灶介入后再行小肠病灶手术切除1例,对症治疗2例.随访：6例十二指肠NETs内镜下切除者均无病生存,11例十二指肠NETs患者术后1例死于心脏疾病,1例死于肺部感染,2例MANEC患者和未行手术治疗的1例NEC患者存活期较短,分别为13个月、10个月、5个月;6例空回肠NETs患者有2例仍然存活,其余4例出现腹腔、肝内广泛播散,均在2年后死亡.结论 小肠神经内分泌肿瘤缺乏特征性临床症状,内镜有助于该病的早期诊断.尽早手术切除肿瘤可提高患者生存率,病理分期和分级与患者的生存预后密切相关.     

Targeting Endothelial Connexin37 Reduces Angiogenesis and Decreases Tumor Growth

Connexin37 (Cx37) and Cx40 form intercellular channels between endothelial cells (EC), which contribute to the regulation of the functions of vessels. We previously documented the participation of both Cx in developmental angiogenesis and have further shown that loss of Cx40 decreases the growth of different tumors. Here, we report that loss of Cx37 reduces (1) the in vitro proliferation of primary human EC; (2) the vascularization of subcutaneously implanted matrigel plugs in Cx37−/− mice or in WT using matrigel plugs supplemented with a peptide targeting Cx37 channels; (3) tumor angiogenesis; and (4) the growth of TC-1 and B16 tumors, resulting in a longer mice survival. We further document that Cx37 and Cx40 function in a collaborative manner to promote tumor growth, inasmuch as the injection of a peptide targeting Cx40 into Cx37−/− mice decreased the growth of TC-1 tumors to a larger extent than after loss of Cx37. This loss did not alter vessel perfusion, mural cells coverage and tumor hypoxia compared to tumors grown in WT mice. The data show that Cx37 is relevant for the control of EC proliferation and growth in different tumor models, suggesting that it may be a target, alone or in combination with Cx40, in the development of anti-tumoral treatments.