Wanzhen Li

<h3>Objective</h3> To determine whether the GGC repeats in the <i>NOTCH2NLC</i> gene contribute to amyotrophic lateral sclerosis (ALS). <h3>Methods</h3> In this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including <i>C9ORF72</i> and <i>ATXN2</i>) and polynucleotide repeat expansions in <i>NOP56</i> and <i>AR</i> genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in <i>NOTCH2NLC</i>. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients. <h3>Results</h3> GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in <i>NOTCH2NLC</i> was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, <i>p</i> = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness–dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration. <h3>Conclusion</h3> Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in <i>NOTCH2NLC</i> is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.

Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.

A mesoporous silica film (MSF) with vertically oriented mesochannels on a conductive substrate serves as a hard-template for electrodeposition of polyaniline (PANI). The PANI nanostructures thus prepared are orderly confined in silica mesochannels, eventually producing a robust hybrid film. The film displays a good electrocatalytic activity toward oxidation of ascorbic acid, and can be used for potentiometric pH sensing with a Nernstian response.