Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia.

Objective: To observe the effects of chimeric antigen receptor T (CAR-T) cell immunotherapy on immune cells and related toxic side effects in patients with refractory acute lymphoblastic leukemia (ALL). Methods: A retrospective study was conducted in 35 patients with refractory ALL. The patients were treated with CAR-T cell therapy in our hospital from January 2020 to January 2021. The efficacy was evaluated at one and three months post treatments. The venous blood of the patients was collected before treatment, 1 month after treatment, and 3 months after treatment. The percentage of regulatory T cells (Treg cells), natural killer (NK) cells, and T lymphocyte subsets (CD3+, CD4+, and CD8+ T cells) was detected by flow cytometry. The ratio of CD4+/CD8+ was calculated. Patient's toxic side effects such as fever, chills, gastrointestinal bleeding, nervous system symptoms, digestive system symptoms, abnormal liver function, and blood coagulation dysfunction were monitored and recorded. The incidence of toxic and side effects was calculated, and the incidence of infection was recorded. Results: After one month of CAR-T cell therapy in 35 patients with ALL, the efficacy evaluation showed that complete response (CR) patients accounted for 68.57%, CR with incomplete hematological recovery (CRi) patients accounted for 22.86%, and partial disease (PD) patients accounted for 8.57%, and the total effective rate was 91.43%. In addition, compared with that before treatment, the Treg cell level in CR+CRi patients treated for 1 month and 3 months decreased prominently, and the NK cell level increased dramatically (P < 0.05). Compared with that before treatment, the levels of CD3+, CD4+, and CD4+/CD8+ in patients with CR+CRi in the 1-month and 3-month groups were markedly higher, and the levels of CD4+/CD8+ in the 3-month group were memorably higher than those in the 1-month group (P < 0.05). During CAR-T cell therapy in 35 patients with ALL, fever accounted for 62.86%, chills for 20.00%, gastrointestinal bleeding for 8.57%, nervous system symptoms for 14.29%, digestive system symptoms for 28.57%, abnormal liver function for 11.43%, and coagulation dysfunction for 8.57%. These side effects were all relieved after symptomatic treatment. During the course of CAR-T therapy in 35 patients with ALL, 2 patients had biliary tract infection and 13 patients had lung infection. No correlations were found between the infection and age, gender, CRS grade, usage of glucocorticoids or tocilizumab, and laboratory indicators such as WBC, ANC, PLT, and Hb (P > 0.05). Conclusion: CAR-T cell therapy had a good effect on patients with refractory ALL by regulating the immune function of the body via mediating the content of immune cells. CAR-T cell therapy may have therapeutic effect on refractory ALL patients with mild side effects and high safety.

Patterns and Trends in Receipt of Opioids Among Patients Receiving Treatment for Cancer in a Large Health System.

BACKGROUND: Given limited evidence on opioid prescribing among patients receiving treatment for cancer during the ongoing opioid epidemic, our objective was to assess predictors of and trends in opioid receipt during cancer treatment, including how patterns differ by type of cancer. METHODS: Using cancer registry data, we identified patients with a first lifetime primary diagnosis of breast, colorectal, or lung cancer from 2013 to 2017 who underwent treatment within a large cancer center network. Cancer registry data were linked to electronic health record information on opioid prescriptions. We examined predictors of and trends in receipt of any opioid prescription within 12 months of cancer diagnosis. RESULTS: The percentage of patients receiving opioids varied by cancer type: breast cancer, 35% (1,996/5,649); colorectal, 37% (776/2,083); lung, 47% (1,259/2,654). In multivariable analysis, opioid use in the year before cancer diagnosis was the factor most strongly associated with receipt of opioids after cancer diagnosis, with 4.90 (95% CI, 4.10-5.86), 5.09 (95% CI, 3.88-6.69), and 3.31 (95% CI, 2.68-4.10) higher odds for breast, colorectal, and lung cancers, respectively. We did not observe a consistent decline in opioid prescribing over time, and trends differed by cancer type. CONCLUSIONS: Our findings suggest that prescription of opioids to patients with cancer varies by cancer type and other factors. In particular, patients are more likely to receive opioids after cancer diagnosis if they were previously exposed before diagnosis, suggesting that pain among patients with cancer may commonly include non-cancer-related pain. Heterogeneity and complexity among patients with cancer must be accounted for in developing policies and guidelines aimed at addressing pain management while minimizing the risk of opioid misuse.

The Vacuolar Pathway of Long Peptide Cross-Presentation Can Be TAP Dependent.

The intracellular pathway of cross-presentation, which allows MHC class I-restricted presentation of peptides derived from exogenous Ags, remains poorly defined and may vary with the nature of the exogenous Ag and the type of APC. It can be cytosolic, characterized by proteasome and TAP dependency, or vacuolar, usually believed to be proteasome and TAP independent. Cross-presentation is particularly effective with long synthetic peptides, and we previously reported that the HLA-A2-restricted cross-presentation of a long peptide derived from melanoma Ag gp100 by human monocyte-derived immature dendritic cells occurred in a vacuolar pathway, making use of newly synthesized HLA-A2 molecules that follow a nonclassical secretion route. In this article, we show that the HLA-A1-restricted cross-presentation of a long peptide derived from tumor Ag MAGE-A3 by human monocyte-derived immature dendritic cells also follows a vacuolar pathway. However, as opposed to the HLA-A2-restricted peptide, cross-presentation of the HLA-A1-restricted peptide is TAP dependent. We show that this paradoxical TAP-dependency is indirect and reflects the need for TAP to load HLA-A1 molecules with peptides in the endoplasmic reticulum, to allow them to escape the endoplasmic reticulum and reach the vacuole, where peptide exchange with the cross-presented peptide likely occurs. Our results confirm and extend the involvement of the vacuolar pathway in the cross-presentation of long peptides, and indicate that TAP-dependency can no longer be used as a key criterion to distinguish the cytosolic from the vacuolar pathway of cross-presentation. They also stress the existence of an alternative secretory route for MHC class I, which will be worthy of further studies.

Under Treatment of Prostate Cancer in Rural Locations.

PURPOSE: Compared to urban populations, rural populations rank poorly on numerous health indicators, including cancer outcomes. We examined the relationship of rural residence with stage and treatment among patients with prostate cancer, the second most common malignancy in men. MATERIALS AND METHODS: Using the Pennsylvania Cancer Registry we identified all men diagnosed with prostate cancer between 2009 and 2015. Patients were classified as residing in a rural area, a large town or an urban area using the Rural-Urban Commuting Area classification. Our primary outcomes included indicators of prostate cancer treatment and treatment types but we also examined disease stage and mortality. We used the chi-square tests to assess differences between groups and estimated multivariable logistic regression models to assess the association between rural residence and treatment. RESULTS: We identified 51,024 men diagnosed with localized or metastatic prostate cancer between 2009 and 2015. The overall incidence of prostate cancer decreased during the study period from 416 to 304/100,000 men while the incidence of metastatic disease increased from 336 to 538/100,000. Rural residents were less likely to undergo treatment than urban residents even when stratified by low, intermediate and high risk disease (aOR 0.77, 95% CI 0.64-0.91; aOR 0.71, 95% CI 0.58-0.89; and aOR 0.68, 95% CI 0.53-0.89, respectively). Rural status did not affect the receipt of radiation therapy compared to other treatment types. CONCLUSIONS: Prostate cancer treatment differs between urban and rural residents. Rural residents are less likely to receive treatment even when stratified by disease risk.

Associations between alcohol intake and diabetic retinopathy risk: a systematic review and meta-analysis.

BACKGROUND: Some previous studies have reported inconsistent results on the association between alcohol intake and diabetic retinopathy (DR) risk. This study aimed to evaluate the potential effects of alcohol intake on subsequent DR risk using a meta-analytic approach. METHODS: Three electronic databases (PubMed, EmBase, and the Cochrane library) were systematically searched for observational studies from their inception till November 2019. The pooled odds ratio (OR) with 95% confidence interval (CI) were applied for the summary effect estimate using a random-effects model. RESULTS: A total of 15 studies (5 cohort studies, 4 case-control studies, and 6 cross-sectional studies) with 37,290 participants and 12,711 DR cases were selected for the final meta-analysis. The pooled OR indicated no significant association between alcohol intake and DR risk (OR: 0.91; 95%CI: 0.78-1.06; P = 0.225), irrespective of the studies being pooled cohort (OR: 0.95; 95%CI: 0.66-1.36; P = 0.761), case-control (OR: 0.97; 95%CI: 0.77-1.23; P = 0.818), or cross-sectional (OR: 0.86; 95%CI: 0.69-1.08; P = 0.190) ones. However, this association might have been affected by the type of diabetes mellitus and the adjusted status. CONCLUSION: The results of this study showed that the potential impact of alcohol intake on DR risk may differ according to the type of diabetes mellitus and adjusted status. Further large-scale, prospective cohort studies should be conducted to verify the findings of this study and to evaluate DR risk in relation to the dose and type of alcohol intake.

Precipitation is the main factor affecting the variation of foliar nitrogen isotope composition in two leguminous shrub species of northwestern China.

An increase in foliar nitrogen isotope composition (δ15N) with decreasing precipitation has been shown to occur widely in non-N2-fixing plant species. However, similar patterns have not been identified in N2-fixing species. Here, we tested the relationships of foliar δ15N with local environmental factors and leaf properties in two leguminous shrub species (Caragana korshinskii and Caragana liouana) sampled from 30 populations. Results indicated that the mean annual precipitation (MAP) primarily accounted for the variation of foliar δ15N in the two species. Further analysis revealed strong negative correlations between foliar δ15N and MAP within and across species. These results suggest that the foliar δ15N of leguminous shrub species also shift along precipitation gradients, which augments our understanding of the relationships between foliar δ15N and climatic factors.

Urban-Rural Differences in Receipt of Cancer Surgery at High-Volume Hospitals and Sensitivity to Hospital Volume Thresholds.

Methods for identifying high-volume hospitals affect conclusions about rural cancer care access.

LncRNA RP11-818O24.3 promotes hair-follicle recovery via FGF2-PI3K/Akt signal pathway.

A previous study indicated that patients with androgenic alopecia (AGA) have significantly reduced levels of LncRNA RP11-818O24.3. This study investigates whether LncRNA RP11-818O24.3 promotes hair-follicle recovery and its possible mechanism. Hair alteration and cutaneous histopathological changes induced by testosterone propionate were observed by H&E and bromodeoxyuridinc (BrdU) stain to evaluate the therapeutic effect of LncRNA RP11-818O24.3 in C57BL/6 J mice. The cellular viability was analyzed in LncRNA RP11-818O24.3-transfected human hair-follicle stem cells (HFSCs) in vitro. The signaling pathways and pro-proliferative factors were investigated by transcriptomic gene sequencing and qRT-PCR. LncRNA RP11-818O24.3 transfection successfully recovered hair growth and hair-follicle cells in AGA mice. In a series of HFSC studies in vitro, LncRNA RP11-818O24.3 transfection greatly promoted cellular proliferation and decreased cellular apoptosis. Transcriptome gene sequencing suggested that the phosphatidylinositol 3-kinase (PI3K)-Akt pathway was upregulated by LncRNA RP11-818O24.3. The qRT-PCR results showed that fibroblast growth factor (FGF)-2 was 14-times upregulated after LncRNA RP11-818O24.3 transfection. Hair-follicle recovery activity of LncRNA RP11-818O24.3 may involve the upregulation of FGF2 and PI3K-Akt to promote follicle stem cell survival. These data not only provide a theoretical basis for AGA development but also reveal a novel therapeutic method for AGA patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-024-00624-3.

Impact of the Affordable Care Act on access to accredited facilities for cancer treatment.

OBJECTIVE: To examine differential changes in receipt of surgery at National Cancer Institute (NCI)-designated comprehensive cancer centers (NCI-CCC) and Commission on Cancer (CoC) accredited hospitals for patients with cancer more likely to be newly eligible for coverage under Affordable Care Act (ACA) insurance expansions, relative to those less likely to have been impacted by the ACA. DATA SOURCES AND STUDY SETTING: Pennsylvania Cancer Registry (PCR) for 2010-2019 linked with discharge records from the Pennsylvania Health Care Cost Containment Council (PHC4). STUDY DESIGN: Outcomes include whether cancer surgery was performed at an NCI-CCC or a CoC-accredited hospital. We conducted a difference-in-differences analysis, estimating linear probability models for each outcome that control for residence in a county with above median county-level pre-ACA uninsurance and the interaction between county-level baseline uninsurance and cancer treatment post-ACA to capture differential changes in access between those more and less likely to become newly eligible for insurance coverage (based on area-level proxy). All models control for age, sex, race and ethnicity, cancer site and stage, census-tract level urban/rural residence, Area Deprivation Index, and year- and county-fixed effects. DATA COLLECTION/EXTRACTION METHODS: We identified adults aged 26-64 in PCR with prostate, lung, or colorectal cancer who received cancer-directed surgery and had a corresponding surgery discharge record in PHC4. PRINCIPAL FINDINGS: We observe a differential increase in receiving care at an NCI-CCC of 6.2 percentage points (95% CI: 2.6-9.8; baseline mean = 9.8%) among patients in high baseline uninsurance areas (p = 0.001). Our estimate of the differential change in care at the larger set of CoC hospitals is positive (3.9 percentage points [95% CI: -0.5-8.2; baseline mean = 73.7%]) but not statistically significant (p = 0.079). CONCLUSIONS: Our findings suggest that insurance expansions under the ACA were associated with increased access to NCI-CCCs.

The Impacts of Planting Patterns Combined with Irrigation Management Practices on Watermelon Growth, Photosynthesis, and Yield.

(1) Background: Crop yields in China's arid and semi-arid regions are limited by water shortages. Exploring the interactions and resource utilization among agroforestry species is key to maintaining diversified agricultural production. (2) Objective: An apple-watermelon agroforestry system and watermelon sole-cropping system were compared to quantify how resource availability (light, water) and watermelon performance (leaf photosynthetic rate, growth, and yield) change with irrigation strategies. (3) Methods: A three-year apple and watermelon field experiment was conducted in a young apple orchard in the arid area of central Ningxia to test the effect of light competition and irrigation systems on light environment, leaf photosynthetic rate, plant growth, and yield in watermelon. The experiment encompassed two planting patterns: (i) apple-watermelon agroforestry (AF) and watermelon sole-cropping (SC) and (ii) three irrigation quotas (W1: 105 mm, W2: 210 mm, and W3: 315 mm). (4) Results: The results show that the agroforestry planting pattern extended the growth period of watermelon and increased the leaf area index. Mean daily shade intensity increased by 16.02% from 2020 to 2022. The land equivalent ratio (LER) was >1 in 2021 and 2022. The SWC, leaf photosynthetic rate, LAI, and yield of watermelon in an agroforestry planting pattern were lower than when in a sole-cropping planting pattern. However, under the W1 irrigation strategy, the total soluble solids of the agroforestry planting pattern were 2.27% higher than those of the sole-cropping pattern, and the yield of the agroforestry planting pattern was 2.59% higher than that of the sole-cropping pattern. Under the W3 irrigation strategy, the average watermelon weight in the agroforestry planting pattern was 2.85% higher than that of the sole-cropping pattern. A path analysis showed that the agroforestry planting pattern can increase the yield by increasing soil water content, which is different from the sole-cropping pattern. (5) Conclusions: The results confirm that the apple-watermelon agroforestry planting pattern reduced watermelon yields. However, the LER of the agroforestry system was greater than 1.0. It is reasonable to plant watermelons in young apple forests.

Epitope hierarchy of spontaneous CD4+ T cell responses to LAGE-1.

NY-ESO-1 and LAGE-1 represent highly homologous cancer-germline Ags frequently coexpressed by many human cancers, but not by normal tissues, except testis. In contrast to NY-ESO-1, little is known about spontaneous immune responses to LAGE-1. In the current study, we report on spontaneous LAGE-1-specific CD4(+) T cells isolated from PBLs of patients with advanced LAGE-1(+)/NY-ESO-1(+) melanoma and directed against three promiscuous and immunodominant epitopes. Strikingly, although the three LAGE-1-derived epitopes are highly homologous to NY-ESO-1-derived epitopes, LAGE-1-specific CD4(+) T cells did not cross-react with NY-ESO-1. LAGE-1-specific CD4(+) T cells produced Th1-type and/or Th2-type cytokines and did not exert inhibitory effects on allogenic T cells. We observed that most patients with spontaneous NY-ESO-1-specific responses exhibited spontaneous CD4(+) T cell responses to at least one of the three immunodominant LAGE-1 epitopes. Additionally, nearly half of the patients with spontaneous LAGE-1-specific CD4(+) T cell responses had circulating LAGE-1-specific Abs that recognized epitopes located in the C-terminal portion of LAGE-1, which is distinct from NY-ESO-1. Collectively, our findings define the hierarchy of immunodominance of spontaneous LAGE-1-specific CD4(+) T cell responses in patients with advanced melanoma. These findings demonstrate the capability of LAGE-1 to stimulate integrated cellular and humoral immune responses that do not cross-react with NY-ESO-1. Therefore, they provide a strong rationale for the inclusion of LAGE-1 peptides or protein in vaccine trials for patients with NY-ESO-1(+)/LAGE-1(+) tumors.

Assessing characteristics of populations seen at Commission on Cancer facilities using Pennsylvania linked data.

Commission on Cancer (CoC) accreditation certifies facilities provide quality care. We assessed differences among patients who do and do not visit CoC facilities using Pennsylvania Cancer Registry data linked to facility records for patients diagnosed with cancer between 2018 and 2019 (n = 87 472). Predicted probabilities from multivariable logistic regression indicated patients in the most advantaged Area Deprivation Index quartiles were more likely to visit CoC facilities (78.0%, 95% confidence interval [CI] = 77.5% to 78.6%) compared with other quartiles. Urban patients (74.1%, 95% CI = 73.8% to 74.4%) were more likely than rural to be seen at a CoC facility (62.7%, 95% CI = 61.2% to 64.2%) as were Hispanic patients (88.0%, 95% CI = 86.7% to 89.3%) and non-Hispanic Black patients (79.1%, 95% CI = 78.1% to 80.0%) compared with White patients (72.0%, 95% CI = 71.7% to 72.4%). Differences in demographics suggest CoC data may underrepresent some groups, including low-income and rural patients.

Insurance Type and Area Deprivation Are Associated With Worse Overall Mortality for Patients With Muscle-invasive Bladder Cancer.

OBJECTIVE: To examine the association of area-level socioeconomic status, rural-urban residence, and type of insurance with overall and cancer-specific mortality among patients with muscle-invasive bladder cancer. METHODS: Using the Pennsylvania Cancer Registry, which collects demographic, insurance, and clinical information on every patient with cancer within the state, we identified all patients diagnosed with non-metastatic muscle-invasive bladder cancer between 2010 and 2016 based on clinical and pathologic staging. We used the Area Deprivation Index (ADI) as a surrogate for socioeconomic status and Rural-Urban Commuting Area codes to classify urban, large town, and rural communities. ADI was reported in quartiles, with 4 representing the lowest socioeconomic status. We fit multivariable logistic regression and Cox models to assess the relationship of these social determinants with overall and cancer-specific survival adjusting for age, sex, race, stage, treatment, rural-urban classification, insurance and ADI. RESULTS: We identified 2597 patients with non-metastatic muscle-invasive bladder cancer. On multivariable analysis, Medicare (hazards ratio [HR] 1.15), Medicaid (HR 1.38), ADI 3 (HR 1.16) and ADI 4 (HR 1.21) were independent predictors of greater overall mortality (all P < 0.05). Female sex and receipt of non-standard treatment were associated with increased overall mortality and bladder cancer-specific mortality. There was no significant difference in both overall and cancer-specific survival between patients who were non-Hispanic White compared to non-White or between those from urban areas, large towns, or rural locations. CONCLUSION: Lower socioeconomic status and Medicare and Medicaid insurance were associated with a greater risk of overall mortality while rural residence was not a significant factor. Implementation of public health programs may help reduce the gap in mortality for low SES at-risk populations.

Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire.

CD4(+) regulatory T cells (Tregs) accumulate at tumor sites and play a critical role in the suppression of immune responses against tumor cells. In this study, we show that two immunodominant epitopes derived from the tumor Ags (TAs) NY-ESO-1 and TRAG-3 stimulate both CD4+ Th cells and Tregs. TA-specific Tregs inhibit the proliferation of allogenic T cells, act in a cell-to-cell contact dependent fashion and require activation to suppress IL-2 secretion by T cells. TRAG-3 and NY-ESO-1-specific Tregs exhibit either a Th1-, a Th2-, or a Th0-type cytokine profile and dot not produce IL-10 or TGF-beta. The Foxp3 levels vary from one Treg clone to another and are significantly lower than those of CD4+CD25high Tregs. In contrast to NY-ESO-1-specific Th cells, the NY-ESO-1-specific and TRAG-3-specific Treg clonotypes share a common TCR CDR3 Vbeta usage with Foxp3+CD4+CD25high and CD4+CD25- T cells and were not detectable in PBLs of other melanoma patients and of healthy donors, suggesting that their recruitment occurs through the peripheral conversion of CD4+CD25- T cells upon chronic Ag exposure. Collectively, our findings demonstrate that the same epitopes spontaneously stimulate both Th cells and Tregs in patients with advanced melanoma. They also suggest that TA-specific Treg expansion may be better impaired by therapies aimed at depleting CD4+CD25high Tregs and preventing the peripheral conversion of CD4+CD25- T cells.

Disparities in geographic access to medical oncologists.

OBJECTIVE: The objective of this study is to identify disparities in geographic access to medical oncologists at the time of diagnosis. DATA SOURCES/STUDY SETTING: 2014-2016 Pennsylvania Cancer Registry (PCR), 2019 CMS Base Provider Enrollment File (BPEF), 2018 CMS Physician Compare, 2010 Rural-Urban Commuting Area Codes (RUCA), and 2015 Area Deprivation Index (ADI). STUDY DESIGN: Spatial regressions were used to estimate associations between geographic access to medical oncologists, measured with an enhanced two-step floating catchment area measure, and demographic characteristics. DATA COLLECTION/EXTRACTION METHODS: Medical oncologists were identified in the 2019 CMS BPEF and merged with the 2018 CMS Physician Compare. Provider addresses were converted to longitude-latitude using OpenCage Geocoder. Newly diagnosed cancer patients in each census tract were identified in the 2014-2016 PCR. Census tracts were classified based on rurality and socioeconomic status using the 2010 RUCA Codes and the 2015 ADI. PRINCIPAL FINDINGS: Large towns and rural areas were associated with spatial access ratios (SPARs) that were 6.29 lower (95% CI -16.14 to 3.57) and 14.76 lower (95% CI -25.14 to -4.37) respectively relative to urban areas. Being in the fourth ADI quartile (highest disadvantage) was associated with a 12.41 lower SPAR (95% CI -19.50 to -5.33) relative to the first quartile. The observed difference in a census tract's non-White population from the 25th (1.3%) to the 75th percentile (13.7%) was associated with a 13.64 higher SPAR (Coefficient = 1.10, 95% CI 11.89 to 15.29; p < 0.01), roughly equivalent to the disadvantage associated with living in the fourth ADI quartile, where non-White populations are concentrated. CONCLUSIONS: Rurality and low socioeconomic status were associated with lower geographic access to oncologists. The negative association between area deprivation and geographic access is of similar magnitude to the positive association between larger non-White populations and access. Policies aimed at increasing geographic access to care should be cognizant of both rurality and socioeconomic status.

Treatment disparities in muscle-invasive bladder cancer: Evidence from a large statewide cancer registry.

OBJECTIVE: To identify patient-level factors that can lead to treatment disparities for muscle invasive bladder cancer, we examine factors associated with receipt of definitive therapy, type of definitive therapy, and neoadjuvant chemotherapy administration in a statewide cohort of muscle-invasive bladder cancer patients. MATERIALS AND METHODS: We identified 2,434 patients diagnosed with non-metastatic muscle-invasive bladder cancer between 2010 and 2015 using the Pennsylvania Cancer Registry. We divided the cohort into three subsamples to examine receipt of treatment: definitive therapy among all muscle-invasive bladder cancer patients (n = 1548), cystectomy (n = 1254) vs. trimodal therapy (n = 294), and neoadjuvant chemotherapy among radical cystectomy patients (n = 1156). Multivariable logistic regression models controlling for patient-level covariates, including insurance status, and socioeconomic disadvantage (based on Area Deprivation Index from census tract data) were estimated to examine factors associated with each treatment outcome. RESULTS: Only 64% of muscle-invasive bladder cancer patients underwent definitive therapy. Those receiving trimodal therapy were more likely to be covered by Medicare than those undergoing cystectomy. Uninsured patients were less likely to undergo definitive treatment and Medicare-insured patients were less likely to undergo cystectomy as their definitive therapy. Patients with greater socioeconomic disadvantage were less likely to receive definitive treatment, undergo cystectomy, or receive neoadjuvant chemotherapy. Over the course of the study period, there was increased neoadjuvant chemotherapy use, but a persistent gap by neighborhood socioeconomic status. CONCLUSIONS: Socioeconomic disadvantage and insurance status are patient-level factors associated with suboptimal treatment for muscle-invasive bladder cancer.

PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients.

The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8(+) T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8(+) T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8(+) T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8(+) T cells, NY-ESO-1-specific CD8(+) T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8(+) T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines. Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1(+) APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8(+) T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8(+) T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8(+) T cell numbers and functions, increasing the likelihood of tumor regression.

Identification of Hub Genes as Potential Prognostic Biomarkers in Cervical Cancer Using Comprehensive Bioinformatics Analysis and Validation Studies.

BACKGROUND: Cervical cancer belongs to one of the most common female cancers; yet, the exact underlying mechanisms are still elusive. Recently, microarray and sequencing technologies have been widely used for screening biomarkers and molecular mechanism discovery in cancer studies. In this study, we aimed to analyse the microarray datasets using comprehensive bioinformatics tools and identified novel biomarkers associated with the prognosis of patients with cervical cancer. METHODS: The differentially expressed genes (DEGs) from Gene Expression Omnibus (GEO) datasets including GSE138080, GSE113942 and GSE63514 were analysed using GEO2R tool. The functional enrichment analysis was performed using g:Profiler tool. The protein-protein interaction (PPI) network construction and hub genes identification were performed using the STRING database and Cytoscape software, respectively. The hub genes were subjected to expression and survival analysis in the cervical cancer. The EdU incorporation and Cell Counting Kit-8 assays were performed to evaluate the effects of hub gene knockdown on the proliferation of cervical cancer cells. RESULTS: A total of 89 overlapping DEGs (63 up-regulated and 26 down-regulated genes) were identified in the microarray datasets. The functional enrichment analysis indicated that the overlapping DEGs were mainly associated with "DNA replication" and "cell cycle". Furthermore, the PPI network analysis revealed that the network contains 87 nodes and 309 edges. Sub-module analysis using the Molecular Complex Detection tool identified 21 hub genes from the PPI network. The expression levels of the 21 hub genes were all up-regulated in the cervical cancer tissues when compared to normal cervical tissues as analysed by GEPIA tool. The survival analysis showed that the low expression of cell division cycle 45 (CDC45), GINS complex subunit 2 (GINS2), minichromosome maintenance complex component 2 (MCM2) and proliferating cell nuclear antigen (PCNA) was significantly correlated with the shorter overall survival of patients with cervical cancer. Moreover, the protein expression levels of GINS2, MCM2 and PCNA, but not CDC45, were significantly up-regulated in the cervical cancer tissues when compared to normal cervical tissues. Finally, knockdown of MCM2 significantly suppressed the proliferation of HeLa and SiHa cells. CONCLUSION: In conclusion, we screened a total of 89 overlapping DEGs from the GEO datasets, and further analysis identified four hub genes (CDC45, GINS2, MCM2 and PCNA) that were likely associated with the prognosis of patients with cervical cancer. MCM2 knockdown repressed the cervical cancer cell proliferation. The current findings may provide novel insights into understanding the pathophysiology of cervical cancer and develop therapeutic targets for patients with cervical cancer.

Effects of the mechanical response of low-permeability sandstone reservoirs on CO2 geological storage based on laboratory experiments and numerical simulations.

Carbon dioxide (CO2) geological storage (CGS) is an effective way for reducing greenhouse emissions. The injection of CO2 into the deep formation changes the pore pressure and effective stresses in the reservoir, thus leading to changes in stress-dependent porosity and permeability. These changes give feedback to the injection rate, migration, storage amount of CO2 in the target reservoir. In this study, we focus on the Liujiagou reservoir, one of the first demonstration CGS project in saline aquifers in the Ordos Basin, China. The mathematical model that defines the relationship between the permeability and the injection pressure (or effective stress) was obtained by laboratory experiments. On this basis, the permeability-stress law was successfully integrated into the thermo-hydro-mechanical (THM) coupled simulator TOUGH2Biot to simulate the feedback between the flow and mechanical response. The improved simulator was used to analyze the effects of reservoir mechanical response on CO2 geological storage efficiency. The modeling results indicated that the mechanical response of the reservoir had little effect on reservoir pore pressure and porosity, but it had a significant effect on reservoir permeability and the migration distance, injection rate, and total storage amount of CO2. The maximum increases in the lateral migration distance of CO2 caused by the reservoir mechanical response reached 13.1% using 5 MPa injection pressure. In addition, the total CO2 storage amount increased by 11.6% after 5 years of continuous CO2 injection. Furthermore, when the injection pressure was greater, the reservoir mechanical response had stronger enhancement effects on CGS. Overall, the results suggested that the reservoir mechanical response during CO2 injection was beneficial for increasing CGS efficiency and emphasized the importance of considering the mechanical response in CGS.