BACKGROUND & AIMS: :The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1alpha expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1alpha expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1alpha expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer.

背景与目标： : 据报道，肿瘤中的低氧环境在胰腺癌的进展中起重要作用。基质细胞和癌细胞之间的相互作用也有助于胰腺癌的恶性行为。在本研究中，我们调查了缺氧刺激是否会影响基质细胞以及胰腺癌细胞。我们的发现表明，缺氧显着提高了胰腺癌 (PK8) 和成纤维细胞 (MRC5) 的HIF-1alpha表达。低氧刺激加速了PK8细胞的侵袭活性，因此，当用低氧MRC5细胞制备的条件培养基 (低氧条件培养基) 培养低氧PK8细胞时，其侵袭能力进一步加快。缺氧条件下PK8细胞MMP-2、MMP-7、MT1-MMP和c-Met表达增加。低氧刺激还增加了MRC5细胞的肝细胞生长因子 (HGF) 分泌，导致PK8细胞中c-Met磷酸化升高。相反，通过从低氧条件培养基中去除HGF，可以降低PK8细胞的癌症侵袭，MMP活性和c-Met磷酸化水平。在免疫组织化学研究中，在周围基质以及胰腺癌细胞中观察到HIF-1alpha表达，因此表明癌症和基质细胞中都存在缺氧。此外，发现基质HGF表达不仅与癌细胞中的基质HIF-1alpha表达显着相关，而且与c-Met表达显着相关。这些结果表明，基质和癌细胞内的缺氧环境激活了HGF/c-Met系统，从而有助于胰腺癌的侵袭性特征。

BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.

背景与目标： : 肿瘤浸润的基质细胞 (TISC) 以及肿瘤本身被认为与肿瘤相关的免疫抑制有关，这是肿瘤逃避免疫监视的关键机制之一。然而，由于TISC在已建立的肿瘤中的比例较小，因此很难制备TISC。因此，被认为与肿瘤相关的免疫抑制有关的细胞通常是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中，我们开发了一种从已建立的肿瘤中直接制备TISC的方法，以分析其功能。使用绿色荧光蛋白 (GFP) 转基因 (Tg) 小鼠和C57BL/6小鼠移植了GFPTg小鼠的骨髓 (BM) 细胞，我们检测到了TISC的三个亚群: 一个与BM衍生的未成熟髓样细胞 (ImC) 相容，另外两个亚群，CD11b(+) 细胞和CD11b(-) 细胞不起源于BM。在gm-csf存在下用肿瘤培养后，包括这些亚群但不是每个亚群的TISC可以抑制anti-CD3诱导的T细胞增殖。在我们的系统中，肿瘤没有直接抑制T细胞反应，但是肿瘤的未知因素会影响TISC的免疫抑制。

BACKGROUND & AIMS: BACKGROUND:We examined loss of heterozygosity (LOH) of the P53 gene in bladder cancer, and investigated the role of the P53 gene on malignant progression of papillary tumors. In addition, the clonality of recurrent bladder cancer was examined. METHODS:LOH of the P53 gene was analyzed in 67 bladder cancers from 47 patients. DNA was extracted from formalin-fixed, paraffin-embedded tissues, amplified by the polymerase chain reaction (PCR) at 3 polymorphic loci in the P53 gene, and analyzed with nonradioisotopic single-strand conformation polymorphism (Non-RI SSCP) analysis. RESULTS:Out of 40 informative samples, LOH was detected in 13 samples, containing 4 of 7 in grade 3 (57%), 9 of 23 in grade 2 (39%), and none of 10 in grade 1 (10%). Statistical significance was observed between the LOH in grades 1 and 2, and in grades 1 and 3. An analysis of 5 cases showing malignant progression revealed that 3 (60%) showed an LOH in the primary tumor, and 2 showed LOH in recurrent tumors, in contrast to LOH found in 3 cases of 19 (16%) not showing malignant progression. Four cases with metachronous recurrence exhibited LOH; 2 at recurrent tumors, 1 only at the initial tumor, and 1 at both tumors. CONCLUSIONS:The alterations of the P53 gene were considered to correlate with tumor grade, and contribute to the malignant progression of bladder cancer. LOH in the P53 gene may serve as a clinical indicator for prognosis in superficial bladder cancer.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Brain tumors (BT) are second only to acute lymphoblastic leukemia as the most prevalent form of pediatric cancer, with BT 5-year survival rates approaching 70%. With increased survival, quality of life has emerged as an essential health outcome. This investigation examines the internal consistency reliability and construct validity of the Pediatric Quality of Life Inventory (PedsQL) Brain Tumor Module. METHODS:The PedsQL 4.0 Generic Core Scales, PedsQL Multidimensional Fatigue Scale, and PedsQL Brain Tumor Module were administered to 99 families. The average age of the 56 boys and 43 girls was 9.76 years (range=2-18 years). The sample included children with tumors located in the posterior fossa/brainstem (N=62, 62.6%), supratentorial (N=15, 15.2%), and midline (N=22, 22.2%). Children were on treatment (N=46, 46.5%), off treatment<12 months (N=19, 19.2%), or off treatment>12 months/long-term survivor (N=34, 34.3%). Treatment included radiation (N=61, 61.6%), surgery (N=83, 83.8%), chemotherapy (N=87, 87.9%), and bone marrow transplant (N=5, 5.1%). RESULTS:Internal consistency reliability was demonstrated for the 24-item PedsQL Brain Tumor Module (average alpha=0.78-0.92, parent proxy-report, n=99; average alpha=0.76-0.87, child self-report, n=51). Construct validity for the PedsQL Brain Tumor Module was supported through an analysis of the intercorrelations with the Generic Core Scales and Fatigue Scale. CONCLUSIONS:The findings provide support for the measurement properties of the PedsQL Brain Tumor Module.

背景与目标：

BACKGROUND & AIMS: :In addition to their role in cellular homeostasis, pathways that regulate autophagy affect both tumorigenesis and tumor response to treatment. Therefore, understanding the regulation of autophagy in treated cancer cells is relevant to the discovery of molecular targets for the development of anti-cancer drugs. Our recent report points to radiation-induced inactivation of the mTOR pathway as an underlying mechanism of radiation-induced autophagy in the human breast cancer cell line MCF-7. Most importantly, radiation-induced inactivation of this pathway was detrimental to cell survival and was associated with reversal of mitochondrial ATPase activity and mitochondrial hyperpolarization, decreased level of eukaryotic initiation factor 4G (eIF4G) and increased phosphorylation of p53. Future analysis of the interrelationship among these events and the role each of them plays in cell survival following radiation will increase our ability to employ the mTOR pathway in anti-cancer therapy.

背景与目标： : 除了它们在细胞内稳态中的作用外，调节自噬的途径还影响肿瘤发生和肿瘤对治疗的反应。因此，了解治疗癌细胞中自噬的调控与发现抗癌药物开发的分子靶标有关。我们最近的报告指出，辐射诱导的mTOR途径失活是辐射诱导的人乳腺癌细胞系MCF-7自噬的潜在机制。最重要的是，辐射诱导的该途径的失活对细胞存活有害，并且与线粒体ATPase活性和线粒体超极化的逆转，真核起始因子4G (eIF4G) 水平降低和p53磷酸化增加有关。对这些事件之间的相互关系以及它们在辐射后的细胞存活中所起的作用的未来分析将提高我们在抗癌治疗中采用mTOR途径的能力。

BACKGROUND & AIMS: BACKGROUND:Transanal resection of benign and selected malignant rectal tumors is a well accepted surgical technique. The use of a stereoscopic microsurgical technique, as originally described by Buess et al in 1984, has been shown to improve the results of standard transanal resection by allowing precise, full thickness resections up to 24 cm from the anal verge. Transanal endoscopic microsurgery (TEM) has failed to gain widespread popularity for two reasons: The proprietary instrument set is expensive and complex ($68,000 and 30 components), and the procedure is difficult to master technically. We present our results with a modification of the TEM instrument that incorporates a standard laparoscope and video camera as well as standard laparoscopic instruments.

METHODS:Four surgeons have been trained to date. Details of the training curriculum are presented. The technique of videoendoscopic transanal tumor resection (VTEM) is described. A prospective data base was maintained of all VTEM cases. This was reviewed for this study to determine indications, operative times, complications and outcomes.

RESULTS:Four surgeons performed 27 VTEM cases between August 1994 and June 1996. The average age was 69 years and the majority (16) of patients were ASA III. Pre-op diagnosis was benign polyp in 25 patients and adenocarcinoma in 2. Average operating time was 127 minutes (49 to 280 minutes), and was longer during a surgeon's first 5 cases and for lesions more than 16 cm from the anal verge. Operative problems were rare (4%) and post-op complications (incontinence 2, late bleeding 1, adenoma recurrence 1) were seen in 15%.

CONCLUSIONS:VTEM can be taught successfully to GI and colorectal surgeons using a format similar to that used for advanced laparoscopic courses. The use of already available laparoscopes and instruments decreases the initial costs of the set-up. Results are good, with low rates of complications and recurrence and a very short hospital stay. The patient benefits from an effective, minimally invasive alternative to open surgery.

背景与目标： 背景 : 经肛门切除良性和选定的恶性直肠肿瘤是一种公认的手术技术。如Buess等人1984年最初描述的那样，使用立体显微外科技术已被证明通过允许从肛门边缘最多24厘米个精确的全厚度切除来改善标准经肛门切除的结果。经肛门内窥镜显微外科手术 (TEM) 未能获得广泛的欢迎，原因有两个: 专有仪器套件昂贵且复杂 (68,000美元和30个组件)，并且该程序在技术上难以掌握。我们通过对TEM仪器的改进来展示我们的结果，该TEM仪器结合了标准的腹腔镜和摄像机以及标准的腹腔镜仪器。
方法 : 迄今为止，已经对四名外科医生进行了培训。介绍了培训课程的详细信息。描述了视频内窥镜经肛门肿瘤切除术 (VTEM) 的技术。保留了所有VTEM病例的前瞻性数据库。本研究对此进行了审查，以确定适应症，手术时间，并发症和结果。
结果 : 四名外科医生在1994年8月和1996年6月之间进行了27例VTEM病例。平均年龄为69岁，大多数 (16) 患者为ASA III。术前诊断为良性息肉25例，腺癌2例。平均手术时间为127分钟 (49至280分钟)，并且在外科医生的前5例病例中较长，并且对于肛门边缘的病变超过16厘米。手术问题很少见 (4%)，15% 术后并发症 (失禁2，晚期出血1，腺瘤复发1)。
结论 :VTEM可以使用类似于高级腹腔镜课程的格式成功地教给GI和结肠直肠外科医生。使用已经可用的腹腔镜和仪器可以降低设置的初始成本。结果良好，并发症和复发率低，住院时间短。患者受益于开放手术的有效，微创替代方法。

BACKGROUND & AIMS: :R1H tumors were irradiated with a single dose of 15 Gy X rays using varying sizes of treatment fields. Damage to tumor cells and tumor stroma was determined separately by analysis of growth delay to ten times treatment volume (GD10vo) and net growth delay. GD10vo comprises irradiation effects on tumor parenchymal cells and on tumor stroma, whereas net growth delay only measures effects on tumor parenchymal cells. Stromal damage was observed to increase with increasing field size; the effect on the tumor parenchymal cells, however, was independent of the field size. An increase of GD10vo of 13 days per cm increase of field size diameter was observed. From this the velocity of neovascularization of the irradiated tumor bed was calculated to be 0.30 to 0.38 mm per day.

背景与目标： : 使用不同大小的治疗场，用15 Gy x射线的单剂量照射R1H肿瘤。通过分析生长延迟至十倍治疗量 (GD10vo) 和净生长延迟，分别确定对肿瘤细胞和肿瘤基质的损害。GD10vo包括对肿瘤实质细胞和肿瘤基质的辐射作用，而净生长延迟仅测量对肿瘤实质细胞的影响。观察到基质损伤随着视野大小的增加而增加; 然而，对肿瘤实质细胞的影响与视野大小无关。观察到每增加cm的场尺寸直径，GD10vo增加13天。由此计算出照射肿瘤床的新血管形成速度为每天0.30至0.38毫米。

BACKGROUND & AIMS: :The biological actions of the insulin-like growth factors, IGF-I and IGF-II, are mediated by the ligand-induced activation of the IGF-I receptor (IGF-IR), a transmembrane heterotetramer linked to the ras-raf-mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)-protein kinase B (PKB)/Akt signal transduction cascades. The Wilms' tumor suppressor gene (wt1) encodes a zinc finger transcription factor, WT1, which has been implicated in various cellular processes including proliferation, differentiation and apoptosis. In the present study we demonstrated that IGF-I modulates the WT1 gene expression in neurally derived PC12 cells in a dose- and time-dependent manner. This effect was mediated through both the MAPK and PI3-kinase signaling pathways, as shown by the ability of the specific inhibitors UO126 and LY294002 to abrogate IGF-I action. Moreover, using RT-PCR and transient transfection assays, we demonstrated that the IGF-I effect was associated with corresponding changes in WT1 mRNA levels and WT1 promoter activity. In addition, the results of the present study revealed that high WT1 levels were associated with the induction of apoptosis, whereas low WT1 levels were correlated with the inhibition of apoptosis, as demonstrated by poly ADP ribose polymerase (PARP) cleavage, Bax expression, Annexin V-FITC staining, and by the use of antisense oligonucleotides against WT1. In summary, our results show that the wt1 gene is a novel target for IGF-I action in neurally derived cells.

背景与目标： : 胰岛素样生长因子igf-i和igf-ii的生物学作用是由配体诱导的igf-i受体 (igf-ir) 激活介导的，与ras-raf-有丝分裂原活化蛋白激酶 (MAPK) 和磷脂酰肌醇3激酶 (PI3K)-蛋白激酶B (PKB)/Akt信号转导级联连接的跨膜异四聚体。Wilmss的肿瘤抑制基因 (wt1) 编码锌指转录因子WT1，该因子与各种细胞过程有关，包括增殖，分化和凋亡。在本研究中，我们证明igf-i以剂量和时间依赖性方式调节神经源性PC12细胞中WT1基因的表达。这种作用通过MAPK和PI3-kinase信号通路介导，如特异性抑制剂UO126和LY294002消除igf-i作用的能力所示。此外，使用rt-pcr和瞬时转染分析，我们证明了igf-i效应与WT1 mRNA水平和WT1启动子活性的相应变化有关。此外，本研究的结果表明，高WT1水平与诱导凋亡有关，而低WT1水平与抑制凋亡有关，如聚ADP核糖聚合酶 (PARP) 切割，Bax表达，Annexin V-FITC染色，并通过使用针对wt1的反义寡核苷酸。总之，我们的结果表明wt1基因是神经源性细胞中igf-i作用的新靶标。

BACKGROUND & AIMS: :Proliferating trichilemmal tumor (PTT) is a rare but morphologically distinct tumor that usually arises on the scalp of elderly women. It is composed of multiple cysts consisting of squamous epithelium with trichilemmal keratinization without granular layer interposition. Vulvar proliferating trichilemmal cyst is very rare, with, to the best of our knowledge, only 3 cases previously reported in the literature. We describe a 39-year-old woman with recurrent PTT on the left labium majus of the vulva, which had been excised from the same side 5 years before. She had a palpable nodule, approximately 2 cm in size, which was firm, mobile, and nontender; without erythema and ulceration; and covered by normal skin on the vulva. There was no inguinal lymphadenopathy. The lesion was removed by wide surgical excision; because of the tissue elasticity, primary closure was possible. The pathology result was reported as proliferating trichilemmal carcinoma with tumor-free margins. Although local recurrence after wide excision is rare, we recommend complete excision for treatment of PTT and long-term follow-up because of the possibility of recurrence.

背景与目标： 增生性毛囊瘤 (PTT) 是一种罕见但形态上不同的肿瘤，通常发生在老年妇女的头皮上。它由多个囊肿组成，由鳞状上皮组成，具有三鞘角化，没有颗粒层插入。外阴增生的毛囊囊肿非常罕见，据我们所知，以前文献中仅报道了3例。我们描述了一名39岁的女性，在外阴的左阴唇上复发性PTT，该女性在5年前从同一侧切除。她有一个可触及的结节，大小约2厘米，坚硬，可移动且不触痛; 没有红斑和溃疡; 外阴被正常皮肤覆盖。无腹股沟淋巴结肿大。通过广泛的手术切除切除病变; 由于组织弹性，可以进行一次闭合。病理结果报告为增殖性毛囊癌，边缘无瘤。尽管广泛切除后的局部复发很少见，但由于复发的可能性，我们建议完全切除治疗PTT并进行长期随访。

BACKGROUND & AIMS: PURPOSE:MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. EXPERIMENTAL DESIGN:DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume. RESULTS:RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival. CONCLUSIONS:Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting.

背景与目标：

BACKGROUND & AIMS: PURPOSE:Tumor genomic profiling (TGP) can reveal secondary findings about inherited disease risks in a patient with cancer. Little is known about how patients with advanced cancer, currently the primary users of TGP, perceive the benefits and harms of secondary germline findings. METHODS:We conducted semistructured interviews with 40 patients with advanced breast, bladder, colorectal, or lung cancer who had TGP. Qualitative interview data were evaluated by using a thematic content analysis approach. RESULTS:Most participants expressed interest in the prospect of learning their secondary germline findings (57%), although a minority was equivocal (29%) or disinterested (14%). Reasons for these preferences varied but were influenced by participants' perceptions of diverse benefits and harms of this information, which they regarded as relevant to themselves; their families; and other patients with cancer, medical science, and society. These attitudes were uniquely shaped by participants' personal disease experiences and health status. CONCLUSION:Many patients with advanced cancer are interested in learning secondary germline findings and hold optimistic and perhaps unrealistic beliefs about the potential health benefits. Patients also have important concerns about clinical and emotional implications of this information. These perceptions are necessary to address to ensure that patients make informed decisions about learning secondary germline findings.

背景与目标：

BACKGROUND & AIMS: :Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R.

背景与目标： : 此处报道的是载有索拉非尼的靶向第四代丙酰胺胺树状分子 (G(4)-PAMAM) 的去唾液酸糖蛋白受体 (asgp-r) 的合成和生物学评估。通过将乳糖酸 (La) 与G(4)-PAMAM树状大分子偶联，然后对游离氨基进行乙酰化 (Ac) 以减少非特异性相互作用，从而获得asgp-r靶向的树状大分子细胞膜。此外，通过另外接枝荧光素 (FITC)，很容易表征目标树状分子Ac-La-G(4)-PAMAM-FITC的内化途径和细胞内命运。在HepG-2和HLE细胞系上进行的体外实验允许研究树状大分子影响细胞活力的能力。共聚焦显微镜和细胞荧光分析证实，与未表达的HLE细胞相比，Ac-La-G(4)-PAMAM-FITC树状聚合物在分化良好且表达asgp-r的人肝癌细胞系HepG-2更高的结合和摄取能力。载有索拉非尼的Ac-La-G(4)-PAMAM-FITC树枝状大分子稳定，并显示出持续的索拉非尼释放。正如细胞毒性研究所证明的那样，与摩尔当量剂量的游离索拉非尼相比，包含在树枝状聚合物中的索拉非尼保持了其有效性，并且能够在一段时间内产生更长的持久效果。这种新的靶向树枝状聚合物似乎是将索拉非尼递送到表达asgp-r的肝癌细胞的合适载体。

BACKGROUND & AIMS: :Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

背景与目标： : 表皮生长因子受体 (EGFR) 的致敏突变可预测对EGFR酪氨酸激酶抑制剂 (TKIs) 的反应，并且第一代和第二代TKIs均可作为晚期EGFR突变型非小细胞肺癌患者的一线治疗选择。在重复活检和血浆循环肿瘤DNA中，最终的耐药性可通过多种机制识别。T790M网守突变负责几乎60% 的病例。许多第三代TKIs正在临床开发中，奥希替尼已获得美国食品药品监督管理局的批准，可用于治疗EGFR T790M突变型肺癌患者的初始EGFR激酶治疗失败。这些新药物的耐药机制正在被确定，并且EGFR突变型肺癌的治疗前景继续发展。EGFR TKIs的序列可能会在未来发生变化，针对耐药性的联合疗法似乎很有希望。

BACKGROUND & AIMS: BACKGROUND:An effective malaria transmission-blocking vaccine (TBV) would be a major advance in the current efforts to eliminate and, ultimately, eradicate malaria. Antibodies against Plasmodium falciparum surface protein, Pfs25, are known to block parasite development in the mosquito vector. However, in initial clinical trials the limited immunogenicity of recombinant Pfs25 protein-in-adjuvant vaccines has been a challenge. METHODS:Novel human adenovirus type 5 (Ad5) vectors were used in heterologous prime boost vaccination strategies to augment the immune response against Pfs25. Specifically, an Ad5 vector that directs expression of full-length, membrane-bound Pfs25 was used as a priming immunization followed by a boost with Ad5 viral particles displaying only the Pfs25 epitope targeted by transmission-blocking antibodies 4B7 and 1D2 (Pfs25 aa 122-134) in hypervariable region 5 of the hexon capsid protein. RESULTS:This heterologous prime-boost vaccine strategy induced antibodies that significantly inhibit P. falciparum transmission to mosquitoes in a standard membrane-feeding assay. Further, immunized mice generated a robust anti-Pfs25 antibody response characterized by higher titer, higher relative avidity and a broader IgG subclass profile than observed with a homologous prime-boost with recombinant Pfs25/alum. CONCLUSION:The data suggest that focusing the immune response against defined epitopes displayed on the viral capsid is an effective strategy for transmission-blocking vaccine development.

背景与目标：

BACKGROUND & AIMS: :MicroRNAs are widely involved in cancer progression by inhibiting the expression levels of oncogenes or tumor suppressor genes, and dysregulation of microRNAs may contribute to tumorigenesis. Here, we found that overexpressed miR-208b can reduce the proliferation of human osteosarcoma cell lines U-2OS and Saos-2 by arresting cell cycle progression. The in vivo xenograft tumors induced by Saos-2 cells overexpressing miR-208b had smaller size and grew more slowly than those induced by the control cells. The mobility of U-2OS or Saos-2 cells was also downregulated by miR-208b. MiR-208b targeted a site in the 3' untranslated region of receptor tyrosine kinase-like orphan receptor 2. Inhibition of receptor tyrosine kinase-like orphan receptor 2 suppresses osteosarcoma metastasis in vitro. Recovering the expression levels of receptor tyrosine kinase-like orphan receptor 2 in miR-208b-overexpressed U-2OS or Saos-2 cells attenuated the inhibitory effects of miR-208b. In addition, the expression levels of miR-208b are significantly reduced in human osteosarcoma tissue samples compared to normal tissue samples, and miR-208b levels correlated inversely with receptor tyrosine kinase-like orphan receptor 2 levels. On these bases, we identified that miR-208b targets receptor tyrosine kinase-like orphan receptor 2 gene by which miR-208b can regulate the development of osteosarcoma.

背景与目标： : MicroRNAs通过抑制癌基因或抑癌基因的表达水平而广泛参与癌症的进展，而microRNAs的失调可能有助于肿瘤的发生。在这里，我们发现过表达的miR-208b可以通过阻止细胞周期进程来U-2OS和Saos-2地减少人骨肉瘤细胞系的增殖。由过表达miR-208b的Saos-2细胞诱导的体内异种移植肿瘤比由对照细胞诱导的肿瘤具有更小的尺寸并且生长更慢。U-2OS或Saos-2细胞的迁移率也被miR-208b下调。MiR-208b靶向受体酪氨酸激酶样孤儿受体2的3' 非翻译区的位点。受体酪氨酸激酶样孤儿受体2的抑制抑制体外骨肉瘤转移。恢复miR-208b-overexpressed U-2OS或Saos-2细胞中受体酪氨酸激酶样孤儿受体2的表达水平减弱了miR-208b的抑制作用。此外，与正常组织样品相比，人骨肉瘤组织样品中miR-208b的表达水平显着降低，并且miR-208b水平与受体酪氨酸激酶样孤儿受体2水平成反比。在此基础上，我们确定了miR-208b靶向受体酪氨酸激酶样孤儿受体2基因，通过该基因miR-208b可以调节骨肉瘤的发展。