BMP/TGF-β signaling as a modulator of neurodegeneration in ALS

This commentary focuses on the emerging intersection between BMP/TGF-β signaling roles in nervous system function and the amyotrophic lateral sclerosis (ALS) disease state. Future research is critical to elucidate the molecular underpinnings of this intersection of the cellular processes disrupted in ALS and those influenced by BMP/TGF-β signaling, including synapse structure, neurotransmission, plasticity, and neuroinflammation. Such knowledge promises to inform us of ideal entry points for the targeted modulation of dysfunctional cellular processes in an effort to abrogate ALS pathologies. It is likely that different interventions are required, either at discrete points in disease progression, or across multiple dysfunctional processes which together lead to motor neuron degeneration and death. We discuss the challenging, but intriguing idea that modulation of the pleiotropic nature of BMP/TGF-β signaling could be advantageous, as a way to simultaneously treat defects in more than one cell process across different forms of ALS.     

通鼻消涕颗粒对慢性鼻窦炎鼻黏膜功能的影响*

目的对医院制剂通鼻消涕颗粒对慢性鼻窦炎鼻黏膜功能是否有调控作用进行临床研究。方法 收集慢性鼻窦炎不伴鼻息肉患者，采用单盲方法随机将患者分为治疗组（通鼻消涕颗粒组）和对照组（克拉霉素片组）。分别给予口服通鼻消涕颗粒和克拉霉素片治疗4周，并对治疗前、治疗2周后、治疗4周后的患者进行糖精试验、鼻部症状VAS评分与鼻内镜Lund Kennedy评分。并采用t检验统计分析。比较服药前、服药后的评分变化。结果 VAS评分提示：治疗组中，治疗2周后、治疗4周后与治疗前相比差异均有统计学意义（P＜0.05），对照组在治疗后的各个阶段与治疗前相比均无明显差异（P＞0.05）。Lund Kennedy评分提示：治疗组在治疗2周后与治疗前无明显差异，但在治疗4周后有明显改善（P＜0.05），对照组则在治疗后各个阶段无明显变化（P＞0.05）。糖精试验提示2组在治疗后2周患者糖精清除时间差异无统计学意义（P＞0.05），但治疗组在治疗4周后患者糖精清除时间低于对照组（P＜0.05）。结论 通鼻消涕颗粒对慢性鼻窦炎的鼻黏膜形态与传输功能有明显改善作用，可以促进鼻黏膜纤毛功能的恢复，并优于克拉霉素片组，且无毒副作用，值得临床上推广应用。     

Germline variant burden in multidrug resistance transporters is a therapy-specific predictor of survival in breast cancer patients

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.