Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

Efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) created using covered stents of different diameters: A systematic review and meta-analysis

PurposeThe purpose of this study was to make a systematic review and meta-analysis to determine the stent diameter (8 mm vs. 10 mm) that conveys better safety and clinical efficacy for transjugular intrahepatic portosystemic shunt (TIPS).Materials and methodsFour databases were used to identify clinical trials published from inception until March 2020. Data were extracted to estimate and compare one-year and three-year overall survivals, hepatic encephalopathy, variceal rebleeding, and shunt dysfunction rates between patients with 8 mm covered stents and those with 10 mm covered stents.ResultsFive eligible studies were selected, which included 489 patients (316 men, 173 women). The 8 mm covered stent group had higher efficacy regarding one-year or three-year overall survival (odds ratio [OR], 2.88; P = 0.003) and (OR, 1.81; P = 0.04) and lower hepatic encephalopathy (OR, 0.69; P = 0.04) compared with 10 mm covered stent group. There were no significant differences in variceal rebleeding rate (OR 0.80; P = 0.67). However, shunt dysfunction was lower in 10 mm covered stent group (OR, 2.26; P = 0.003).ConclusionsOur results suggest that the use of 8 mm covered stents should be preferred to that of 10 mm covered stents for TIPS placement when portal pressure is frequently monitored.     

Collimating micro-lens fiber array for noncontact near-infrared diffuse correlation tomography

Near-infrared diffuse correlation spectroscopy/tomography (DCS/DCT) has recently emerged as a noninvasive measurement/imaging technology for tissue blood flow. In DCT studies, the high-dense collection of light temporal autocorrelation curves (g₂(τ)) via fiber array are critical for image reconstruction of blood flow. Previously, the camera-based fiber array limits the field of view (FOV), precluding its applications on large-size human tissues. The line-shape fiber probe based on lens combination, which is predominantly used in current DCT studies, requires rotated-scanning over the surface of target tissue, substantially prolonging the measurement time and increasing the system instability. In this study, we design a noncontact optical probe for DCT based on collimating micro-lens fiber array, termed as FA-nc-DCT system. For each source/detector fiber, a single optical path was collimated by coupling with one micro-lens in the fiber array that is integrated in a square-shape base. Additionally, an 8×8 optical switch is used to share the hardware laser and detectors without spatial scanning. The FA-nc approach for the precise collection of g₂(τ) curves was validated through a speed-varied phantom experiment and the human experiments of cuff occlusion, from which the expected value of the blood flow index (BFI) was obtained. Furthermore, the flow anomaly in the phantom and the ischemic muscle in human were accurately reconstructed from the FA-nc-DCT system, which is combined with the imaging framework based on the Nth-order linear algorithm that we recently created. Those outcomes demonstrated the great potential of FA-nc-DCT technology for fast and robust imaging of various diseases such as human breast cancers.     

“三全育人”视角下思政教育机制实践与探索——“杏林成长导师”计划的构建

“三全育人”是高校思政教育工作的关键一环，也是中医药高校推动思政教育的重要内容。以“三全育人”为视角对北京中医药大学思想政治教育举措“杏林成长导师”计划路径、内容深入分析，运用统计分析和文献研究方法，剖析该计划对中医学专业大学生的学业、思想和实践等多个层面的现实成效，从而为“三全育人”理念在中医药院校制度建构中的应用提供新的视角与方法。     

潜伏期脑胎盘率对预测新生儿不良结局的价值

目的 探讨低危单胎的足月妊娠自然临产后，潜伏期脑胎盘率(CPR)对预测新生儿不良结局的价值。方法 选取2018年1月至2021年3月我院住院临产分娩的673例孕妇为研究对象，测量胎儿大脑中动脉、脐动脉血流参数，获得分娩结局及新生儿结局。参考既往研究得出的不同孕周CPR正常参考值百分位作为分组指标(CPR≤10%参考值定为低CPR)。比较低CPR组(72例)与正常CPR组(601例)两组妊娠结局、新生儿不良结局。结果 低CPR组与正常CPR组在孕妇年龄、孕龄、产次、孕期体质量增长、总产程、新生儿体质量的构成上差异均无统计学意义(P>0.05)。低CPR组因胎儿窘迫行剖宫产或助产发生率、新生儿任一不良结局发生率、新生儿不良结局率均高于正常CPR组，差异均有统计学意义(P<0.05)。低CPR预测新生儿不良结局的准确率为89.5%(602/673),敏感度为51.7%(15/29),特异度为91.1%(587/644)。结论 本研究数据显示，对于无并发症及合并症、低风险的单胎足月妊娠，潜伏期低CPR与新生儿不良结局相关。     

Polyvictimization and Psychiatric Sequelae Associated with Female Genital Mutilation/Cutting (FGM/C)

Female Genital mutilation/cutting (FGM/C) is associated with enduring psychiatric complications. In this study, we investigate the rates of co-morbid abuses and polyvictimization experienced by survivors of FGM/C. This is a sub-analysis of a cohort study examining the patient population at the EMPOWER Center for Survivors of Sex Trafficking and Sexual Violence in New York City. A retrospective chart-review of electronic medical records was conducted for all consenting adult patients who had FGM/C and had an intake visit between January 16, 2014 and March 6, 2020. Of the 80 participants, ages ranged from 20 to 62 years with a mean of 37.4 (SD?=?9.1) years. In addition to FGM/C, participants were victims of physical abuse (43; 53.8%), emotional abuse (35; 43.8%), sexual abuse (35; 43.8%), forced marriage (20; 25%), child marriage (13; 16.3%), and sex trafficking (1; 1.4%). There was a high degree of polyvictimization, with 41 (51.2%) experiencing 3 or more of the aforementioned abuses. Having FGM/C on or after age 13 or having a higher total abuse score was also found to be strong predictors of depression and PTSD. The high rates of polyvictimization among survivors of FGM/C are associated with development of depression and PTSD. Despite co-morbid abuses, patients still attribute substantial psychiatric symptoms to their FGM/C. Health care providers should understand the high risk of polyvictimization when caring for this patient population.

     

Experimental study on the biocompatibility and osteogenesis induction ability of PLLA/DDM scaffolds

Odontology - To investigate the characterization and function of a novel porous osteogenic material (PLLA / DDM) containing polylactic acid and demineralized dentin matrix. The surface morphology...