Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.
identify trends associated with incidence of high risk endometrial cancers in native versus US Asians. Methods Data were obtained from the United States Cancer Statistics and Republic of China Cancer Registry from 2001-2017. We defined high risk cancers as grade 3 endometrial (G3E), serous, clear cell, and carcinosarcoma. SEER*Stat 8.3.9.2 and Joinpoint regression program 4.9.0.0 were used to calculate trends. Results Of 55,031 endometrial cancer patients, 28,204 (51%) were US and 26,827 (49%) were native Asians. In subset, serous cancer incidence (per 100,000) in 2017 was highest in US Asians (serous 1.25, G3E 1.15, carcinosarcoma 0.82) whereas G3E was over four fold higher than other cells types in native Asians (G3E 2.63, serous 0.64, carcinosarcoma 0.51). Over the 17 year study period, the incidence of high risk cancers increased annually at 2.3% in US Asians (serous increase: 6.3%) compared to 21.9% in native Asians (G3E increase: 14.8%) (p<0.001). In analyzing mortality trends, US Asians had a higher annual increase in mortality compared to native Asians (+2.11% vs -2.99%). US Asians had an over two fold higher risk of death for ages 70+ at 22.9 (per 100,000) compared to 10.6 in native Asians. Conclusions The incidence for high risk uterine cancer is increasing significantly more in the Republic of China vs. US. However, mortality rates are higher in the US. Further research is needed to better understand the social determinants and regional differences that may contribute to these trends.
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