Tumor mutational burden adjusted by neutrophil-to-lymphocyte ratio serves as a potential biomarker for atezolizumab-treated patients with extensive stage small cell lung cancer.

BACKGROUND: There is a desperate for the identification of more accurate and efficient biomarkers for ICI responses in patients with SCLC. METHODS: The data of our study was obtained from IMpower133 study. A total of 202 patients with SCLC received the treatment of placebo plus carboplatin plus etoposide (EC) while a total of 201 patients with SCLC received the treatment of atezolizumab plus EC. Overall survival (OS) was compared using Kaplan Meier analyses. Univariate and multivariate Cox regression analysis were used to determine independent prognostic variables affecting OS in patients with SCLC. RESULTS: We have demonstrated that a higher TMB adjusted by a lower neutrophil-to-lymphocyte ratio (NLR) is significantly correlated with improved OS, in patients with SCLC subject to either atezolizumab or placebo (P = 0.001 for atezolizumab and P = 0.034 for placebo). Moreover, Cox model showed that TMB < 10 mut/Mb adjusted by NLR ≥ median was an independent factor of OS for atezolizumab-treated SCLC patients (hazard ratio [HR], 2.82; 95% confidence interval; 1.52-5.24; P = 0.001). Both univariate and multivariate cox regression analysis showed that for patients with SCLC harboring low NLR and high TMB, survival is significantly longer in those treated with atezolizumab than those treated with placebo. Survival benefit is significantly higher in atezolizumab-treated patients with SCLC than those treated with placebo (P = 0.018 for TMB cutoff = 10 mut/Mb, P = 0.034 for TMB cutoff = 16 mut/Mb). CONCLUSION: Our findings provide a promising insight into the utility of NLR-adjusted TMB in the prognosis and immune responses in patients with SCLC.

Structural elucidation of how ARF small GTPases induce membrane tubulation for vesicle fission.

The ADP-Ribosylation Factor (ARF) small GTPases have been found to act in vesicle fission through a direct ability to tubulate membrane. Here, we have used cryo-electron microscopy (EM) to solve the structure of an ARF6 protein lattice assembled on tubulated membrane to 3.9 Å resolution. ARF6 forms tetramers that polymerize into helical arrays to form this lattice. We identify, and confirm functionally, protein contacts critical for this lattice formation. The solved structure also suggests how the ARF amphipathic helix is positioned in the lattice for membrane insertion, and how a GTPase-activating protein (GAP) docks onto the lattice to catalyze ARF-GTP hydrolysis in completing membrane fission. As ARF1 and ARF6 are structurally conserved, we have also modeled ARF1 onto the ARF6 lattice, which has allowed us to pursue the reconstitution of Coat Protein I (COPI) vesicles to confirm more definitively that the ARF lattice acts in vesicle fission. Our findings are notable for having achieved the first detailed glimpse of how a small GTPase bends membrane and having provided a molecular understanding of how an ARF protein acts in vesicle fission.

Immediate and short-term effects of continuous theta burst transcranial magnetic stimulation over contralesional premotor area on post-stroke spasticity in patients with severe hemiplegia: Study protocol for a randomized controlled trial.

Background: Post-stroke spasticity is an important complication that greatly affects survivors' functional prognosis and daily activities. Increasing evidence points to aberrant contralesional neuromodulation compensation after brain injury as a possible culprit for increased spasticity in patients with severe stroke. Hyperactivity of the contralesional premotor area (cPMA) was supposed to be highly correlated with this progression. This study aims to demonstrate the immediate and short-term efficacy of continuous theta-burst stimulation (cTBS) targeting cPMA on upper limb spasticity in severe subacute stroke patients. Methods: This trial is a single-center, prospective, three-group randomized controlled trial. Forty-five eligible patients will be recruited and randomized into three groups: the sham-cTBS group (sham cTBS targeting contralesional PMA), the cTBS-cM1 group (cTBS targeting contralesional M1), and the cTBS-cPMA group (cTBS targeting contralesional PMA). All subjects will undergo comprehensive rehabilitation and the corresponding cTBS interventions once a day, five times a week for 4 weeks. Clinical scales, neurophysiological examinations, and neuroimaging will be used as evaluation tools in this study. As the primary outcome, clinical performance on muscle spasticity of elbow/wrist flexor/extensors and upper-limb motor function will be evaluated with the modified Ashworth scale and the Fugl-Meyer Assessment of Upper Extremity Scale, respectively. These scale scores will be collected at baseline, after 4 weeks of treatment, and at follow-up. The secondary outcomes were neurophysiological examinations and Neuroimaging. In neurophysiological examinations, motor evoked potentials, startle reflex, and H reflexes will be used to assess the excitability of the subject's motor cortex, reticulospinal pathway, and spinal motor neurons, respectively. Results of them will be recorded before and after the first cTBS treatment, at post-intervention (at 4 weeks), and at follow-up (at 8 weeks). Neuroimaging tests with diffusion tensor imaging for all participants will be evaluated at baseline and after the 4-week treatment. Discussion: Based on the latest research progress on post-stroke spasticity, we innovatively propose a new neuromodulation target for improving post-stroke spasticity via cTBS. We expected that cTBS targeting cPMA would have significant immediate and short-term effects on spasticity and related neural pathways. The effect of cTBS-cPMA may be better than that of cTBS via conventional cM1. The results of our study will provide robust support for the application of cTBS neuromodulation in post-stroke spasticity after a severe stroke. Clinical trial registration: This trial was registered with chictr.org.cn on June 13, 2022 (protocol version). http://www.chictr.org.cn/showproj.aspx?proj=171759.