The change of FeNO is correlated with asthma control and lung function.

Objective: To investigate the changes in fractional exhaled nitric oxide (FeNO) after treatment and the association between FeNO changes and the prognosis and lung function of children with asthma. Methods: A total of 144 children newly enrolled with non-standardized treatment of asthma were recruited between September 2020 and December 2021. The children were divided into two groups according to the initial FeNO (0 day), and the changes in FeNO after Budesonide/Formoterol Inhalation Powder Mist (B/FIPM) treatment were observed in different subgroups in correlation with future outcomes after 1 year (well controlled or partly controlled) and lung function. Results: The study showed that B/FIPM therapy significantly reduced FeNO levels and eosinophils (EOS) counts, improving pulmonary function (P < 0.01). FeNO levels significantly decreased in the well controlled group after 1 week treatment but not after 2 weeks. The partly controlled group showed sustained benefits after 2 weeks treatment (P < 0.01). Besides, among the patients with initial FeNO ≤35 ppb, the proportion of well controlled outcome was significantly higher in the group of ΔFeNO >0 (72.73 %) than that in the ΔFeNO ≤0 group (53.85 %) (P = 0.042). Conclusion: B/FIPM is effective in reducing FeNO levels and EOS counts and restoring lung function in children with asthma. In addition, post-treatment changes in FeNO were predictive of prognosis and correlated with post-treatment lung function.

Multifunctional nanoparticles potentiate in-situ tumor vaccines via reversing insufficient Photothermal therapy by disrupting tumor vasculature.

Photothermal therapy can trigger immunogenic cell death and release personalized in-situ tumor vaccine, activating immune responses to eliminate systemic tumors beyond the irradiated zone. However, the immune response of the in-situ tumor vaccines is often undermined by the residual tumor cells and their induced immunosuppressive tumor microenvironment (TME), which is attributed to insufficient photothermal effects stemming from the limited accumulation of photosensitizers. To overcome these limitations, we developed multi-functional nanoparticles (VI@Gd-NPs) that integrate a tumor vasculature-specific disrupting agent (Vadimezan, Phase III clinical drug), a photosensitizer (Indocyanine Green, ICG), and a magnetic resonance imaging contrast agent (Gadolinium, Gd) through chemical self-assembly. By selectively disrupting the tumor vasculature, these nanoparticles enhance the intratumoral delivery of photosensitizers (ICG and blood cells), and Gd. With the guidance of Gd-enhanced MRI, the improved delivery facilitates comprehensive photothermal ablation and regulates the TME, further initiating the in-situ tumor vaccine. Notably, this approach significantly enhances anti-tumor immune responses, improves survival rates, and reduces tumor recurrence and metastasis in various animal models. Moreover, depleting CD8+ T cells reverses these therapeutic benefits, highlighting the critical role of adaptive T cell immunity. Therefore, the VI@Gd-NPs treatment holds great potential for reigniting the in-situ tumor vaccine of photothermal therapy.

Site Effect of Electron Acceptors on Ultralong Organic Room-Temperature Phosphorescence.

Herein, we successfully observe the site effect of electron acceptors on ultralong organic room-temperature phosphorescence (UORTP) in the case of 7H-benzo[c]carbazole (BCz) derivatives: cyanophenyl on the nitrogen site can promote intersystem crossing (ISC) efficiency and enhance phosphorescence intensity by facilitating n-π* transitions but make a slight change to the phosphorescence wavelength; cyanophenyl on the naphthalene site can cause a remarkable red shift of phosphorescence wavelength by reducing the T1 energy level of BCz derivatives and also enhance phosphorescence intensity by promoting ISC but weaken phosphorescence intensity by lowering the molecular symmetry. Three BCz derivatives (1-BCzPhCN, 2-BCzPhCN, and 3-BCzPhCN) with the electron acceptor cyanophenyl at different sites (nitrogen site and naphthalene site) were synthesized through a combination of the nucleophilic substitution reaction and the Suzuki coupling reaction. The phosphorescence properties of 1-BCzPhCN, 2-BCzPhCN, and 3-BCzPhCN in toluene solution, in a copolymerized MMA film, and in a PVA film were measured and analyzed. 1-BCzPhCN emits intrinsic green ultralong phosphorescence at ∼500, ∼536, and ∼580 nm, while 2-BCzPhCN and 3-BCzPhCN give out intrinsic yellow ultralong phosphorescence with a red shift of 27 and 40 nm, showing that cyanophenyl on the naphthalene site leads to a remarkable red shift of the intrinsic phosphorescence wavelength, but cyanophenyl on the nitrogen site makes a slight difference to the intrinsic phosphorescence wavelength. Under the same condition, the phosphorescence intensity is usually ranked as 1-BCzPhCN/3-BCzPhCN > 2-BCzPhCN, demonstrating that cyanophenyl on the nitrogen site promotes ISC and enhances phosphorescence intensity, but cyanophenyl on the naphthalene site reduces molecular symmetry and accelerates nonradiative dissipation. Time-dependent density functional theory calculations verify that cyanophenyl on the naphthalene site shifts the phosphorescence wavelength by reducing the T1 energy level, and cyanophenyl on the nitrogen site facilitates n-π* transitions to strengthen the phosphorescence intensity. Moreover, three BCz derivatives were doped into DMAP and BBP, separately. The BCz derivatives exhibited different phosphorescence colors and shifts due to interactions with the host materials. We believe this work will give an insight into the structure-property relationship of organic phosphorescence molecules and pave a way for design of colorful UORTP materials.

Population Health Implications of Medicaid Prerelease and Transition Services for Incarcerated Populations.

Policy Points A large population of incarcerated people may be eligible for prerelease and transition services under the new Medicaid Reentry Section 1115 Demonstration Opportunity. We estimated the largest relative population increases in Medicaid coverage from the opportunity may be expected in smaller and more rural states. We found that mental illness, hepatitis C, and chronic kidney disease prevalence rates were sufficiently high among incarcerated populations to likely skew overall Medicaid population prevalence of these diseases when prerelease and transition services are expanded, implying the need for planning of additional data exchange and service delivery infrastructure by state Medicaid plans. CONTEXT: As states expand prerelease and transition services for incarcerated individuals under the Medicaid Reentry Section 1115 Demonstration Opportunity, we sought to systematically inform Medicaid state and plan administrators regarding the population size and burden of disease data available on incarcerated populations in both jails and prisons in the United States. METHODS: We analyzed data on eligibility criteria for new Medicaid prerelease and transition services based on incarceration length and health conditions across states. We estimated the potentially eligible populations in prisons and jails, considering various incarceration lengths and health status requirements. We also compared disease prevalence in the incarcerated population with that of the existing civilian Medicaid population. FINDINGS: We found that rural and smaller states would experience a disproportionately large proportion of their Medicaid populations to be eligible for prerelease and transition services if new Medicaid eligibility rules were broadly applied. Self-reported psychological distress was notably higher among incarcerated individuals compared with those currently on Medicaid. The prevalence rates of previously diagnosed chronic hepatitis C and kidney disease were also much higher in the incarcerated population than the existing civilian Medicaid population. CONCLUSIONS: We estimated large volumes of potentially Medicaid-eligible entrants as coverage policy changes take effect over the coming years, particularly impacting smaller and more rural states. Our findings reveal very high disease prevalence rates among the incarcerated population subject to new Medicaid coverage, including specific chronic, infectious, and behavioral health conditions that state Medicaid programs, health plans, and providers may benefit from advanced planning to address.

Efficacy of photodynamic therapy using 5-aminolevulinic acid-induced photosensitization is enhanced in pancreatic cancer cells with acquired drug resistance.

The use of 5-aminolevulinic acid (ALA) as a precursor for protoporphyrin IX (PpIX) is an established photosensitization strategy for photodynamic therapy (PDT) and fluorescence guided surgery. Ongoing studies are focused on identifying approaches to enhance PpIX accumulation as well as to identify tumor sub-types associated with high PpIX accumulation. In this study, we investigated PpIX accumulation and PDT treatment response with respect to nodule size in 3D cultures of pancreatic cancer cells (Panc1) and a derivative subline (Panc1OR), which has acquired drug resistance and exhibits increased epithelial mesenchymal transition. In monolayer and 3D culture dose response studies the Panc1OR cells exhibit significantly higher cell killing at lower light doses than the drug naïve cells. Panc1OR also exhibits increased PpIX accumulation. Further analysis of cell killing efficiency per molecule of intracellular PpIX indicates that the drug resistant cells are intrinsically more responsive to PDT. Additional investigation using exogenous delivery of PpIX also shows higher cell killing in drug resistant cells, under conditions which achieve approximately the same intracellular PpIX. Overall these results are significant as they demonstrate that this example of drug-resistant cells associated with aggressive disease progression and poor clinical outcomes, show increased sensitivity to ALA-PDT.

Mass incarceration as a driver of the tuberculosis epidemic in Latin America and projected effects of policy alternatives: a mathematical modelling study.

BACKGROUND: Tuberculosis incidence is increasing in Latin America, where the incarcerated population has nearly quadrupled since 1990. We aimed to quantify the impact of historical and future incarceration policies on the tuberculosis epidemic, accounting for effects in and beyond prisons. METHODS: In this modelling study, we calibrated dynamic compartmental transmission models to historical and contemporary data from Argentina, Brazil, Colombia, El Salvador, Mexico, and Peru, which comprise approximately 80% of the region's incarcerated population and tuberculosis burden. The model was fit independently for each country to incarceration and tuberculosis data from 1990 to 2023 (specific dates were country dependent). The model does not include HIV, drug resistance, gender or sex, or age structure. Using historical counterfactual scenarios, we estimated the transmission population attributable fraction (tPAF) for incarceration and the excess population-level burden attributable to increasing incarceration prevalence since 1990. We additionally projected the effect of alternative incarceration policies on future population tuberculosis incidence. FINDINGS: Population tuberculosis incidence in 2019 was 29·4% (95% uncertainty interval [UI] 23·9-36·8) higher than expected without the rise in incarceration since 1990, corresponding to 34 393 (28 295-42 579) excess incident cases across countries. The incarceration tPAF in 2019 was 27·2% (20·9-35·8), exceeding estimates for other risk factors like HIV, alcohol use disorder, and undernutrition. Compared with a scenario where incarceration rates remain stable at current levels, a gradual 50% reduction in prison admissions and duration of incarceration by 2034 would reduce population tuberculosis incidence by over 10% in all countries except Mexico. INTERPRETATION: The historical rise in incarceration in Latin America has resulted in a large excess tuberculosis burden that has been under-recognised to date. International health agencies, ministries of justice, and national tuberculosis programmes should collaborate to address this health crisis with comprehensive strategies, including decarceration. FUNDING: National Institutes of Health.

Numerical Analysis in Double-Sided Polishing: Mechanism Exploration of Edge Roll-Off.

Understanding the mechanism of stress concentration effects on the surface of semiconductor substrate materials-silicon wafers-in Double-Sided Polishing (DSP) is particularly important for improving polishing quality. In this study, a two-dimensional finite element model is established to study the effect of contact state and stress concentration during polishing on edge roll-off (ERO) and polishing rate uniformity. The variation in this contact state is influenced by changes in wafer thickness and the gap between it and the carrier. The model is validated by experiments and helps to further analyze and interpret the experimental results, identifying six stages of contact states during the polishing process. The research indicates that the phenomenon of stress concentration at the edge of a wafer is caused by the pads creating a large amount of compression at the edge of the wafer. Additionally, there appears to be a threshold value during the polishing process, below which the stress concentration on the wafer changes, thereby altering the magnitude of edge roll-off and, ultimately, affecting overall flatness. This study provides a basis for optimizing the process design.

Population suppression by release of insects carrying a dominant sterile homing gene drive targeting doublesex in Drosophila.

CRISPR homing gene drives can suppress pest populations by targeting female fertility genes, converting wild-type alleles into drive alleles in the germline of drive heterozygotes. fsRIDL (female-specific Release of Insects carrying a Dominant Lethal) is a self-limiting population suppression strategy involving continual release of transgenic males carrying female lethal alleles. Here, we propose an improved pest suppression system called "Release of Insects carrying a Dominant-sterile Drive" (RIDD), combining performance characteristics of homing drive and fsRIDL. We construct a split RIDD system in Drosophila melanogaster by creating a 3-gRNA drive disrupting the doublesex female exon. Drive alleles bias their inheritance in males, while drive alleles and resistance alleles formed by end-joining cause dominant female sterility. Weekly releases of RIDD males progressively suppressed and eventually eliminated cage populations. Modeling shows that RIDD is substantially stronger than SIT and fsRIDL. RIDD is also self-limiting, potentially allowing targeted population suppression.

Identification of novel pQTL-SNPs associated with lung adenocarcinoma risk: A multi-stage study.

BACKGROUND AND OBJECTIVE: To explore the association between protein quantitative trait loci (pQTL-SNPs) and the risk of LUAD. METHODS: "Blood +" high depth blood proteomics analysis was performed on plasma from female LUAD patients and female healthy controls, and combined with proteomics data from tumors and adjacent non-tumor tissues of female LUAD patients to screen proteins uniformly expressed in plasma and tissues. pQTL-SNPs were then screened through multiple databases and subjected to multilevel screening. The associations between selected pQTL-SNPs and LUAD risk were evaluated by Female Lung Cancer Consortium in Asia GWAS (FLCCA GWAS). Enzyme linked immunosorbent assay (ELISA) is used to determine the levels of candidate protein. RESULTS: A total of 7 pQTL-SNPs were significantly associated with altered LUAD risk (p < 0.05). Meanwhile, the expression of their corresponding target proteins were all decreased in both plasma and tumor tissues of LUAD cases, which may play a role of tumor suppressor proteins. After mutation of 3 pQTL-SNPs (rs7683000, rs73224660, and rs2776937), the expression of corresponding target proteins BST1 and NRP1 decreased, and as potential tumor suppressor proteins, which may promote tumorigenesis and further increasing the risk of developing LUAD (OR >1, p < 0.05); while after mutation the other pQTL-SNP rs62069916, the corresponding target protein APOH expression was increased, while as a potential tumor suppressor protein, which may inhibit tumorigenesis and further reduced the risk of developing LUAD (OR <1, p < 0.05). In addition, the expression of NRP1 and APOH were significant decreased in LUAD cell lines and validated in plasma of LUAD patients. CONCLUSION: A total of 4 pQTL-SNPs (rs7683000, rs73224660, rs2776937, and rs62069916) may associate with altered LUAD risk by regulating the expression of target proteins (BST1, NRP1, and APOH) after mutation.

Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models.

Interactions between tumor and stromal cells are well known to play prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs, though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use time lapse imaging and image analysis to study how co-culture geometry impacts interactions between epithelial and stromal cells. We show that extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1) result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility. We analyze these interactions in co-cultures using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. We further contrast co-cultures of PANC1 with those containing a drug resistant subline (PANC1-OR) previously established in our lab and find that heterotypic cell-cell interactions are suppressed in the latter relative to the parental line. We use RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also correlated with reduction in the hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation.

Population suppression with dominant female-lethal alleles is boosted by homing gene drive.

BACKGROUND: Methods to suppress pest insect populations using genetic constructs and repeated releases of male homozygotes have recently been shown to be an attractive alternative to older sterile insect techniques based on radiation. Female-specific lethal alleles have substantially increased power, but still require large, sustained transgenic insect releases. Gene drive alleles bias their own inheritance to spread throughout populations, potentially allowing population suppression with a single, small-size release. However, suppression drives often suffer from efficiency issues, and the most well-studied type, homing drives, tend to spread without limit. RESULTS: In this study, we show that coupling female-specific lethal alleles with homing gene drive allowed substantial improvement in efficiency while still retaining the self-limiting nature (and thus confinement) of a lethal allele strategy. Using a mosquito model, we show the required release sizes for population elimination in a variety of scenarios, including different density growth curves, with comparisons to other systems. Resistance alleles reduced the power of this method, but these could be overcome by targeting an essential gene with the drive while also providing rescue. A proof-of-principle demonstration of this system in Drosophila melanogaster was effective in both biasing its inheritance and achieving high lethality among females that inherit the construct in the absence of antibiotic. CONCLUSIONS: Overall, our study shows that substantial improvements can be achieved in female-specific lethal systems for population suppression by combining them with various types of gene drive.

Efficacy and safety of hyaluronic-polidocanol foam in sclerotherapy for head and neck venous malformations.

Background: Foam sclerotherapy is currently the first-line treatment for venous malformations (VMs). Hyaluronic acid-polidocanol (HA-POL) foam has been used in the treatment of head and neck VMs recently; however, its clinical efficacy and safety have yet to be further evaluated, and the impact of age and other related factors on its safety is still unclear. Objective: To assess the efficacy and safety of HA-POL foam in the treatment of head and neck VMs. Methods and materials: We performed a single-center retrospective review of all patients with VMs involving the head and neck region undergoing HA-POL foam sclerotherapy from February 2015 to February 2022 in the Oral and Maxillofacial Surgery Department of Qilu Hospital Shandong University. Patients' medical records were collected and all patients enrolled were followed up for 1-6 months (group 1), part of them were followed up for 3-9 years (group 2). Results: A total of 223 patients with head and neck VMs were enrolled in the study, with 36 patients who were followed for 3-9 years. Total response rate in group 1 was 96.41% (n = 215), of which 30.94% (n = 69) of the patients met the criteria of "resolution," and 65.47% (n = 146) of the patients had "significant improvement." In group 2, the total response rate was 72.22% (n = 26), of which the rates of the patients met the criteria of "resolution" and patients had "significant improvement" were all 36.11% (n = 13)0.144 (64.57%) patients experienced complications like localized swelling, pain and fever, and no serious complications occurred. The risk of developing complications after treatment was independent of age, and was weakly associated with the dose of HA-POL foam. Conclusion: The HA-POL foam sclerotherapy is safe and effective in the treatment of head and neck VMs.

Identification of biomarkers associated with pathological tumor staging and their utility in the diagnosis and prognosis of prostate cancer.

OBJECTIVE: Pathological tumor (pT) staging plays a crucial role in prostate cancer (PCa) diagnosis. This study aimed to identify pT stage-associated biomarkers and explored their utility in PCa prognosis. METHODS: GSE69223 was used to identify potential targets differentially expressed between level 2 of pT staging (pT2) and level 3 of pT staging (pT3). Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were performed on tissues from patients with PCa to screen the pT stage-associated targets and to explore the prognostic value of these targets in PCa. RESULTS: CENPI and SLC38A11 were most significantly upregulated, whereas ANO6 and KANK2 were mostly decreased in pT3 tumors compared with pT2 staging. ANO6 levels were negatively associated with preoperative prostate-specific antigen (PSA) levels, lymph node staging (N staging), Gleason score, and overall survival (OS); CENPI was positively associated with preoperative PSA levels, N staging, and OS, but was not associated with the Gleason score; SLC38A11 and KANK2 were not associated with OS. ANO6 and KANK2 were correlated with neutrophil markers, whereas CENPI was correlated with macrophage M2 types. CONCLUSION: We identified 4 reliable PCa biomarkers associated with pT staging that would be valuable for diagnosing and determining PCa prognosis.

A structured biomimetic nanoparticle as inflammatory factor sponge and autophagy-regulatory agent against intervertebral disc degeneration and discogenic pain.

Lower back pain (LBP) is a common condition closely associated with intervertebral disc degeneration (IDD), causing a significant socioeconomic burden. Inflammatory activation in degenerated discs involves pro-inflammatory cytokines, dysregulated regulatory cytokines, and increased levels of nerve growth factor (NGF), leading to further intervertebral disc destruction and pain sensitization. Macrophage polarization is closely related to autophagy. Based on these pathological features, a structured biomimetic nanoparticle coated with TrkA-overexpressing macrophage membranes (TMNP@SR) with a rapamycin-loaded mesoporous silica core is developed. TMNP@SR acted like sponges to adsorbe inflammatory cytokines and NGF and delivers the autophagy regulator rapamycin (RAPA) into macrophages through homologous targeting effects of the outer engineered cell membrane. By regulating autophagy activation, TMNP@SR promoted the M1-to-M2 switch of macrophages to avoid continuous activation of inflammation within the degenerated disc, which prevented the apoptosis of nucleus pulposus cells. In addition, TMNP@SR relieved mechanical and thermal hyperalgesia, reduced calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the dorsal root ganglion, and downregulated GFAP and c-FOS signaling in the spinal cord in the rat IDD model. In summary, TMNP@SR spontaneously inhibits the aggravation of disc inflammation to alleviate disc degeneration and reduce the ingress of sensory nerves, presenting a promising treatment strategy for LBP induced by disc degeneration.

Ethanol foam: a novel type of foam sclerosant for treating venous malformations.

Introduction: Sclerotherapy is a commonly utilized treatment approach for venous malformations. Absolute ethanol is renowned for its remarkable efficacy as a potent sclerosants, but it is potentially associated with severe complications. Foam sclerotherapy is considered superior to liquid sclerotherapy owing to its heightened efficacy and diminished incidence of complications. Thus, our objective was to devise an ethanol foam sclerosant that delivers exceptional efficacy while mitigating complications. Methods: In the first set of experiments, we identified the suitable range of ethanol concentrations for sclerotherapy through human umbilical vein endothelial cell proliferation assays and blood clotting experiments. Next, the surfactants polysorbate 80, egg yolk lecithin, and hyaluronic acid were added to create stable ethanol foam, with their ratios meticulously optimized. Results: The optimal concentration range of ethanol was determined to be 30-60%. Eventually, a 48% ethanol foam was successfully produced with excellent stability. Other than ethanol, the formulation included 5 × 10-3 g/mL polysorbate 80, 10-2 g/mL egg yolk lecithin, and 0.04 mL/mL hyaluronic acid. Discussion: The novel ethanol foam produced here could be a promising candidate for the treatment of venous malformations.

Mass incarceration as a driver of the tuberculosis epidemic in Latin America and projected impacts of policy alternatives: A mathematical modeling study.

Background: Tuberculosis incidence is increasing in Latin America, where the incarcerated population has nearly quadrupled since 1990. The full impact of incarceration on the tuberculosis epidemic, accounting for effects beyond prisons, has never been quantified. Methods: We calibrated dynamic compartmental transmission models to historical and contemporary data from Argentina, Brazil, Colombia, El Salvador, Mexico, and Peru, which comprise approximately 80% of the region's incarcerated population and tuberculosis burden. Using historical counterfactual scenarios, we estimated the transmission population attributable fraction (tPAF) for incarceration and the excess population-level burden attributable to increasing incarceration prevalence since 1990. We additionally projected the impact of alternative incarceration policies on future population tuberculosis incidence. Findings: Population tuberculosis incidence in 2019 was 29.4% (95% UI, 23.9-36.8) higher than expected without the rise in incarceration since 1990, corresponding to 34,393 (95% UI, 28,295-42,579) excess incident cases across countries. The incarceration tPAF in 2019 was 27.2% (95% UI, 20.9-35.8), exceeding estimates for other risk factors like HIV, alcohol use disorder, and undernutrition. Compared to a scenario where incarceration rates remain stable at current levels, a gradual 50% reduction in prison admissions and duration of incarceration by 2034 would reduce population tuberculosis incidence by over 10% in all countries except Mexico. Interpretation: The historical rise in incarceration in Latin America has resulted in a large excess tuberculosis burden that has been under-recognized to-date. International health agencies, ministries of justice, and national tuberculosis programs should collaborate to address this health crisis with comprehensive strategies, including decarceration. Funding: National Institutes of Health.

Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models.

Interactions between tumor and stromal cells are well known to play a prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs. Though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use 3D co-culture geometries to recapitulate juxtacrine interactions between epithelial and stromal cells. In particular, extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1), result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility which leads to highly condensed macroscopic multicellular aggregates as detected using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. To investigate how drug resistance impacts these juxtacrine interactions we contrast cultures in which PANC1 are substituted with a drug resistant subline (PANC1-OR) previously established in our lab. We find that heterotypic cell-cell interactions are highly suppressed in drug-resistant cells relative to the parental PANC1 cells. To investigate further we conduct RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also consistent with loss of hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation.

Specific CD4+ T cell phenotypes associate with bacterial control in people who 'resist' infection with Mycobacterium tuberculosis.

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ- T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4+ T cells showed enrichment of TH17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these TH17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype.

Plasma GPI and PGD are associated with vascular normalization and may serve as novel prognostic biomarkers for lung adenocarcinoma: Multi-omics and multi-dimensional analysis.

The aim of this study was to explore potential novel plasma protein biomarkers for lung adenocarcinoma (LUAD). A plasma proteomics analysis was carried out and candidate protein biomarkers were validated in 102 LUAD cases and 102 matched healthy controls. The same LUAD tumor tissues were detected to explore the correlation between the expression of candidate proteins in tissues and plasma and vascular normalization. A LUAD active metastasis mice model was constructed to explore the role of candidate proteins for lung metastasis. GPI and PGD were verified to be upregulated in plasma from LUAD patients, and the expression of GPI in tumor tissue was positively correlated with the expression of GPI in plasma and negatively correlated with the normalization of tumor blood vessels. Meanwhile, a negative correlation between the expression of GPI and PGD in plasma and tumor vascular normalization was discovered. In the LUAD active metastasis model, the lowest levels of vascular normalization and the highest expression of GPI and PGD were found in mice with lung metastases. This study found that GPI and PGD may be potential plasma biomarkers for LUAD, and monitoring those may infer the risk of metastasis and malignancy of the tumor. SIGNIFICANT: We identified GPI and PGD as potential novel diagnostic and prognostic biomarkers for LUAD. PGD and GPI can be used as diagnostic biomarkers in combination with other available strategies to assist in the screening and diagnosis of LUAD, and as prognostic biomarkers aid in predict the risk of tumor metastasis and malignancy in patients with LUAD.