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Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated macrophage (TAM) infiltration, contributing to T cell inhibition, and this was further augmented upon radiation. Intratumoral knockdown (KD) of Serpinb3a resulted in tumor growth inhibition and reduced CXCL1 and S100A8/A expression and MDSC and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy (RT). We further revealed that SERPINB3 promoted STAT-dependent expression of chemokines, whereby inhibition of STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/ A9 expression in SERPINB3 cells. Patients with elevated pretreatment SCCA levels and high phosphorylated STAT3 (p-STAT3) had increased intratumoral CD11b+ myeloid cells compared with patients with low SCCA levels and p-STAT3, who had improved overall survival after RT. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract immunosuppression and improve the response to RT.

Active topological defects are one of the most exciting non-equilibrium systems of recent times. In our experiments, we confine an active nematic populated by positive and negative topological defects to a toroidal surface, and explore how the local geometry, parameterised by the Gaussian curvature, influences the distribution of defects. We find curvature-induced defect unbinding, for relatively thick tori and low activities. In contrast, for high activity and thin tori, which serve to locally approach the cylindrical limit, the relevance of the defect-curvature coupling is lost. Overall, our results illustrate how curvature and activity can both be used to affect how defects distribute on surfaces with varying curvature. [ABSTRACT FROM AUTHOR]

Objectives: Many behavioral health providers (BHPs) in primary care practices spend a majority of their time addressing mental health rather than behavior change. We wanted to better understand the practice of BHPs in integrated primary care. Methods: Survey of BHPs from practices participating in the Colorado State Innovation Model (SIM) initiative. The survey measured what diagnoses BHPs receive referrals to treat, what they treat regardless of referral reason, which techniques they use, and think are most effective for mental health diagnoses and behavior change/weight management support, and their interest in providing support for weight management. Results were analyzed using descriptive statistics and Spearman correlations. Results: We received 79 surveys representing 64 out of 248 SIM practices (practice response rate of 26%). BHPs reported addressing health-related behaviors with patients referred to them for mental health diagnoses. They expressed interest in health behavior and believed the techniques they use for traditional mental health diagnoses also support behavior change. Most reported using cognitive behavioral therapy (89%), mindfulness (94%), and relaxation/stress management (94%). Time in practice was associated with receiving more referrals for weight management (rho(76) = .271, P = .018) and with addressing diet (rho(75) = .339, P = .003) and weight management (rho(75) = .323, P = .005). BHPs in practices that had care managers were more likely to report receiving referrals for weight management than BHPs in practices that did not employ a case manager ( r τ (76) = .222, P = .038); practices employing a health coach were more likely to receive referrals for physical activity than practices without a health coach ( r τ (76) = .257, P = .015). Conclusions: BHPs are interested in and frequently address health related behavior. Formalizing health behavior services from BHPs in primary care may provide opportunities to better support patients with behavior change and subsequently improve health outcomes.

BackgroundThis study investigated the spatial relationship of 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography ([18F]FDG-PET) standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs) derived from magnetic resonance (MR) diffusion imaging on a voxel level using simultaneously acquired PET/MR data. We performed an institutional retrospective analysis of patients with newly diagnosed cervical cancer who received a pre-treatment simultaneously acquired [18F]FDG-PET/MR. Voxel SUV and ADC values, and global tumor metrics including maximum SUV (SUVmax), mean ADC (ADCmean), and mean tumor-to-muscle ADC ratio (ADCT/M) were compared. The impacts of histology, grade, and tumor volume on the voxel SUV to ADC relationship were also evaluated. The potential prognostic value of the voxel SUV/ADC relationship was evaluated in an exploratory analysis using Kaplan-Meier/log-rank and univariate Cox analysis.ResultsSeventeen patients with PET/MR scans were identified. There was a significant inverse correlation between SUVmax and ADCmean, and SUVmax and ADCT/M. In the voxelwise analysis, squamous cell carcinomas (SCCAs) and poorly differentiated tumors showed a consistent significant inverse correlation between voxel SUV and ADC values; adenocarcinomas (AdenoCAs) and well/moderately differentiated tumors did not. The strength of the voxel SUV/ADC correlation varied with metabolic tumor volume (MTV). On log-rank analysis, the correlation between voxel SUV/ADC values was prognostic of disease-free survival (DFS).ConclusionsIn this hypothesis-generating study, a consistent inverse correlation between voxel SUV and ADC values was seen in SCCAs and poorly differentiated tumors. On univariate statistical analysis, correlation between voxel SUV and ADC values was prognostic for DFS.

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

Purpose To evaluate the targetability of late-stage cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-induced hyperthermia (HT) as an adjuvant to radiation therapy (RT). Methods Seventy-nine cervical cancer patients (stage IIIB–IVA) who received RT with lesions visible on positron emission tomography-computed tomography (PET-CT) were retrospectively analyzed for targetability using a commercially-available HT-capable MRgHIFU system. Targetability was assessed for both primary targets and/or any metastatic lymph nodes using both posterior (supine) and anterior (prone) patient setups relative to the transducer. Thirty-four different angles of rotation along subjects’ longitudinal axis were analyzed. Targetability was categorized as: (1) Targetable with/without minimal intervention; (2) Not targetable. To determine if any factors could be used for prospective screening of patients, potential associations between demographic/anatomical factors and targetability were analyzed. Results 72.15% primary tumors and 33.96% metastatic lymph nodes were targetable from at least one angle. 49.37% and 39.24% of primary tumors could be targeted with patient laying in supine and prone positions, respectively. 25°–30° rotation and 0° rotation had the highest rate of the posterior and anterior targetability, respectively. The ventral depth of the tumor and its distance to the coccyx were statistically correlated with the anterior and posterior targetability, respectively. Conclusion Most late-stage cervical cancer primaries were targetable by MRgHIFU HT requiring either no/minimal intervention. A rotation of 0° or 25°–30° relative to the transducer might benefit anterior and posterior targetability, respectively. Certain demographic/anatomic parameters might be useful in screening patients for treatability.

The thermal decomposition and ignition of high-performance high explosives occur via a mechanism where the solid phase sublimes and the parent molecules decompose rapidly in the gas phase to form unstable and charged intermediates. These intermediates continue to react and form the final products to release energy and do work. We have observed that the presence of electromagnetic energy significantly reduces the ignition temperature of a common high explosive, and data suggest that this occurs via electromagnetic interactions with the charged gas-phase intermediates. Here, we modified the thermal decomposition kinetic expressions for octogen (High Melt eXplosive, HMX) to couple the effects of an incident microwave (MW) field. This modified kinetic model is used to investigate our previous experimental work which showed that the surface temperature at ignition of HMX powder is reduced by the MW field. The Fridman–Macheret α-model is a common approach in plasma chemistry and was incorporated into the Henson/Smilowitz HMX kinetics; this effectively reduces the activation energy (Ea) by vibronically excited charged reactive intermediates. A modified kinetic model was implemented into the COMSOL Multiphysics Software. The thermal time to ignition was validated; as a result, plasma formation reduced the surface temperature by ∼23 °C compared to thermal ignition. With a validated kinetic model that can simulate both pure thermal ignition and mixed thermal/plasma ignition, we are able to simulate our previous experimental work showing that plasma ignition reduces the surface temperature at ignition compared to thermal initiation. [ABSTRACT FROM AUTHOR]

Longitudinal cohort studies of HIV and substance use disorders play an important role in understanding these conditions, but high rates of attrition can threaten their integrity and generalizability. This study aimed to identify factors associated with attrition in a 5-year observational cohort study of 469 individuals with and without HIV infection and methamphetamine (MA) dependence. Rates of attrition in our four study groups were approximately 24% in HIV-MA-, 15% in HIV+MA-, 56% in HIV-MA+, and 47% in HIV+MA+ individuals. Predictors of attrition in the overall cohort included history of MA, alcohol, and other substance dependence, learning impairment, reduced cognitive reserve, and independence in activities of daily living (all ps < 0.05), but varied somewhat by clinical group. Of particular note, enrollment in a neuroimaging sub-study was associated with significantly boosted rates of retention in the MA groups. Results from this investigation highlight the complexity of the clinical factors that influence retention in cohort studies of HIV-infected MA users and might guide the development and implementation of targeted retention efforts.

Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (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 with patients with HPV 16+ tumors, consistent with previously published studies. Using RNA sequencing 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 to our knowledge, transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional data set (n = 88) and within the HPV 16+ subset (n = 36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct mechanisms dependent upon p53–p21. 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.

The microstructure of organic mixed ionic–electronic conductors (OMIECs) plays a crucial role in their functionality. OMIECs are generally polycrystalline conjugated polymers consisting of a complex arrangement of disordered and ordered regions. While considerable research has focused on structural transformations in the ordered regions of OMIECs upon ion insertion, the evolution of disordered regions is difficult to probe. Here, we explore changes in the disordered conjugated polymer regiorandom (RRa) poly(3-hexylthiophene) (P3HT), focusing on its response to repeated electrochemical doping/dedoping cycles and thermal annealing. By performing a series of cyclic voltammograms (CVs) followed by grazing incidence wide angle X-ray scattering (GIWAXS), we show how the molecular packing and microstructure of RRa P3HT change. Additionally, we employ nanoscale infrared imaging via photoinduced force microscopy (PiFM) to visualize the changes in polymer morphology and the distribution of ions within the polymer matrix. Our results indicate that RRa P3HT experiences significant structural reorganization after repeated doping/dedoping cycles. These large structural rearrangements lead to partially irreversible doping due to ion trapping in electronically disconnected polymer regions. Moreover, we observe that electrochemical cycling followed by thermal annealing promotes crystallinity in RRa P3HT, yielding GIWAXS diffractograms akin to those of polycrystalline regioregular (RR) P3HT. Our research conclusively shows that disordered conjugated polymers can undergo substantial structural and morphological transformations through repeated electrochemical doping, leading to enhanced ordering and ion trapping within the polymer matrix. [ABSTRACT FROM AUTHOR]

AISI 8620H steel is one of the most widely used carburizing alloy steels for a variety of medium-strength applications including gears, camshafts, fasteners, chains, and pins[1]. Flexibility in carburization treatments [...]

PurposeThis pilot study was performed to evaluate whether tumor uptake of (18)F-labeled 3'-deoxy-3'fluorothymidine (FLT), a proliferative radiotracer, at baseline and early during therapy, is predictive of outcome in locally advanced rectal cancer.ProceduresFourteen patients underwent positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and FLT before therapy and PET with FLT approximately 2 weeks after initiating neoadjuvant chemoradiotherapy. FLT and FDG uptake were evaluated qualitatively and by maximum standardized uptake value (SUV(max)). Tumor FLT and FDG uptake were correlated with disease-free survival (DFS).ResultsThirteen patients underwent surgery after therapy, one died before surgery with progressive disease. FDG-PET/computed tomography detected regional lymph node metastases in five and FLT-PET was positive in one. High pretherapy FDG uptake (SUV(max) ≥ 14.3), low during-therapy FLT uptake (SUV(max)