Numerical simulations of the linear and nonlinear two-dimensional Navier-Stokes equations, and linear stability theory are used to parametrically investigate hypersonic boundary layers over ultrasonic absorptive coatings. The porous coatings consist of a uniform array of rectangular pores (slots) with a range of porosities and pore aspect ratios. For the numerical simulations, temporally (rather than spatially) evolving boundary layers are considered and we provide evidence that this approximation is appropriate for slowly growing second-mode instabilities. We consider coatings operating in the typical regime where the pores are relatively deep and acoustic waves and second-mode instabilities are attenuated by viscous effects inside the pores, as well as regimes with phase cancellation or reinforcement associated with reflection of acoustic waves from the bottom of the pores. These conditions are defined as attenuative and cancellation/reinforcement regimes, respectively. The focus of the present study is on the cases which have not been systematically studied in the past, namely the reinforcement regime (which represents a worst-case scenario, i.e. minimal second-mode damping) and the cancellation regime (which corresponds to the configuration with the most potential improvement). For all but one of the cases considered, the linear simulations show good agreement with the results of linear instability theory that employs an approximate porous-wall boundary condition, and confirm that the porous coating stabilizing performance is directly related to their acoustic scattering performance. A particular case with relatively shallow pores and very high porosity showed the existence of a shorter-wavelength instability that was not initially predicted by theory. Our analysis shows that this new mode is associated with acoustic resonances in the pores and can be more unstable than the second mode. Modifications to the theoretical model are suggested to account for the new mode and to provide estimates of the porous coating parameters that avoid this detrimental instability. Finally, nonlinear simulations confirm the conclusions of the linear analysis; in particular, we did not observe any tripping of the boundary layer by small-scale disturbances associated with individual pores.

Severe and prolonged lymphopenia frequently occurs in patients with glioblastoma after standard chemoradiotherapy and has been associated with worse survival, but its underlying biological mechanism is not well understood. To address this, we performed a correlative study in which we collected and analyzed peripheral blood of patients with glioblastoma ( n  = 20) receiving chemoradiotherapy using genomic and immune monitoring technologies. RNA sequencing analysis of the peripheral blood mononuclear cells (PBMC) showed an elevated concentration of myeloid-derived suppressor cell (MDSC) regulatory genes in patients with lymphopenia when compared with patients without lymphopenia after chemoradiotherapy. Additional analysis including flow cytometry and single-cell RNA sequencing further confirmed increased numbers of circulating MDSC in patients with lymphopenia when compared with patients without lymphopenia after chemoradiotherapy. Preclinical murine models were also established and demonstrated a causal relationship between radiation-induced MDSC and systemic lymphopenia using transfusion and depletion experiments. Pharmacological inhibition of MDSC using an arginase-1 inhibitor (CB1158) or phosphodiesterase-5 inhibitor (tadalafil) during radiation therapy (RT) successfully abrogated radiation-induced lymphopenia and improved survival in the preclinical models. CB1158 and tadalafil are promising drugs in reducing radiation-induced lymphopenia in patients with glioblastoma. These results demonstrate the promise of using these classes of drugs to reduce treatment-related lymphopenia and immunosuppression.

Persistent HPV infection is causative for the majority of cervical cancer (CC) cases; however, current guidelines do not require HPV testing for newly diagnosed CC. Using an institutional cohort of 88 CC patients treated uniformly with standard-of-care chemoradiation (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared to patients with HPV 16 positive tumors, consistent with previously published studies.Using RNAseq analysis we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas (n=304). For the first time transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional dataset (n=88), and within the HPV 16 positive subset (n=36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct p53-p21 dependent mechanisms. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy and these patients may benefit from alternative treatment strategies.

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Numerical simulations of the linear and nonlinear two-dimensional Navier-Stokes equations are used to parametrically investigate hypersonic boundary layers over ultrasonic absorptive coatings consisting of a uniform array of rectangular pores (slots) with a range of porosities and pore aspect ratios. Based on our previous work, we employ a temporally evolving approximation appropriate to slowly-growing second-mode instabilities. We consider coatings operating in attenuative regimes where the pores are relatively deep and acoustic waves and second mode instabilities are attenuated by viscous effects inside the pores, as well as cancellation/reinforcement regimes with alternating regions of local minima and maxima of the coating acoustic absorption, depending on the frequency of the acoustic waves. The focus is on reinforcement cases which represent a worst case scenario (minimal second-mode damping). For all but one of the cases considered, the linear simulations confirm the results of linear instability theory that employs an approximate porous-wall boundary condition. A particular case with a relatively shallow cavities and very high porosity showed the existence of a shorter wavelength instability that is not predicted by theory. Finally, nonlinear simulations of the same cases led to the same conclusions as linear analysis; in particular, we did not observe any "tripping" of the boundary layer by small scale disturbances associated with individual pores.