Interleukin-27 Promotes the Generation of Myeloid-derived Suppressor Cells to Alleviate Graft-versus-host Disease.

BACKGROUND: Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. METHODS: In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. RESULTS: In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. CONCLUSIONS: Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy.

Exploring the convergence of ICT, digital financial inclusion, environmental pressures, and free trade and their significance in driving sustainable green investment initiatives under carbon neutrality targets.

Due to its rapid economic development over the past few decades, China is now at the forefront of environmental issues, necessitating creative solutions that combine ICT, digital financial inclusion, environmental pressure, and free trade to encourage green investment. This study aims to investigate the linkage between ICT, digital financial inclusion, environmental pressure, free trade, and green investment in China from 1996 to 2022 by employing the Partial least squares structural equation modelling (PLS-SEM). As per our results, the statistical values of Cronbach's alpha, composite reliability, and average variance are all above the cutoff point, demonstrating the applicability of this methodology. According to the structural model's results, the path coefficients between digital financial inclusion and green investment, environmental pressure and green investment, and GDP and green investment are positively significant, implying that these three factors are crucial for boosting green investment in China. In addition, our vector autoregressive model results suggest that ICT, digital financial inclusion, environmental pressures, free trade, and GDP cause green investment to rise in China. Thus, the policymakers in China should focus on developing comprehensive policies to encourage green investment in China, which is crucial for economic and environmental sustainability.

Granulomatous lobular mastitis co-existing with ductal carcinoma in situ: Report of three cases and review of the literature.

Granulomatous lobular mastitis (GLM) is a benign and infrequent chronic breast ailment. Although this lesion can be clinically and radiographically mistaken for early-onset breast cancer, it is a rare occurrence for the two to coexist. This report describes three such cases. In all three patients, the primary signs and symptoms were related to the formation of diffuse breast masses or abscesses. Breast ultrasound and MRI revealed glandular edema and dilated breast ducts. The biopsies of all lesions exhibited both granulomatous inflammation confined to the lobules of the breast, abundant interstitial inflammatory cell infiltrates, and apparently cancerous cells located in dilated ducts with intact basement membranes. The surgically excised specimens confirmed the diagnosis of GLM and ductal carcinoma in situ (DCIS) in all three patients who underwent breast mass resection. By clinical imaging and clinical manifestations, GLM may obscure a concurrent DCIS, as highlighted by the cases reported herein.

CAR-Aptamers Enable Traceless Enrichment and Monitoring of CAR-Positive Cells and Overcome Tumor Immune Escape.

Chimeric antigen receptor (CAR)-positive cell therapy, specifically with anti-CD19 CAR-T (CAR19-T) cells, achieves a high complete response during tumor treatment for hematological malignancies. Large-scale production and application of CAR-T therapy can be achieved by developing efficient and low-cost enrichment methods for CAR-T cells, expansion monitoring in vivo, and overcoming tumor escape. Here, novel CAR-specific binding aptamers (CAR-ap) to traceless sort CAR-positive cells and obtain a high positive rate of CAR19-T cells is identified. Additionally, CAR-ap-enriched CAR19-T cells exhibit similar antitumor capacity as CAR-ab (anti-CAR antibody)-enriched CAR-T cells. Moreover, CAR-ap accurately monitors the expansion of CAR19-T cells in vivo and predicts the prognosis of CAR-T treatment. Essentially, a novel class of stable CAR-ap-based bispecific circular aptamers (CAR-bc-ap) is constructed by linking CAR-ap with a tumor surface antigen (TSA): protein tyrosine kinase 7 (PTK7) binding aptamer Sgc8. These CAR-bc-aps significantly enhance antitumor cytotoxicity with a loss of target antigens by retargeting CAR-T cells to the tumor in vitro and in vivo. Overall, novel CAR-aptamers are screened for traceless enrichment, monitoring of CAR-positive cells, and overcoming tumor cell immune escape. This provides a low-cost and high-throughput approach for CAR-positive cell-based immunotherapy.

Does postcholecystectomy increase the risk of colorectal cancer?

With the increasing number of cholecystectomy and the high proportion of colorectal cancer in malignant tumors, the question of whether cholecystectomy is a risk factor for colorectal disease has been widely concerned. After reviewing the literature at home and abroad, the authors will summarize the research progress of the correlation between the occurrence of colorectal tumors after cholecystectomy, in order to provide help for the prevention and treatment of colorectal tumors.

IL-27 Gene Therapy Induces Stat3-Mediated Expansion of CD11b+Gr1+ Myeloid Cells and Promotes Accumulation of M1 Macrophages in the Tumor Microenvironment.

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment.

CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor-associated myeloid cells.

CD200 is overexpressed in many solid tumors and considered as an immune checkpoint molecule dampening cancer immunity. In this study, we found that CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. scRNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effector cells are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling regulates the expression of chemokines in tumor-associated myeloid cells (TAMCs). In the absence of CD200R, TAMCs increased expression of CCL24 and resulted in increased infiltration of eosinophils, which contributes to anti-tumor activity. Overall, we conclude that CD200R signaling contributes to unfavorable TME through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has implications in developing CD200-CD200R targeted immunotherapy of solid tumors.

Exposure to p-dichlorobenzene and prevalent endocrine-related reproductive cancers among US women.

P-dichlorobenzene (p-DCB) is a pest repellent and air deodorant that is commonly found in the household and public buildings. Exposure to p-DCB has been suggested to have potential metabolic and endocrine effects. Little is known about its association with endocrine-related female cancers. In this cross-sectional study, a nationally representative subsample of 4459 women, aged 20 years or older, in the 2003-2016 National Health and Nutrition Examination Survey was analyzed for the association between p-DCB exposure, measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), the primary metabolite of p-DCB, and prevalent endocrine-related female cancers (defined as breast, ovarian, and uterine cancers) using multivariate logistic regression models, adjusting for potential confounders. Of the study participants, 202 women (weighted prevalence, 4.20%) reported being diagnosed with any of these endocrine-related reproductive cancers. Women with reproductive cancers showed a statistically significant increase in urinary 2,5-DCP concentrations (weighted geometric mean, 7.97 vs. 5.84 µg/g creatinine; p < 0.0001), compared to women without these cancers. After adjusting for potential confounders, we found that women in the moderate (1.94- < 28.10 µg/g creatinine) and high level (≥ 28.10 µg/g creatinine) of 2,5-DCP had significantly increased odds of endocrine-related reproductive cancers (odds ratio of 1.66 (95% CI: 1.02, 2.71) and 1.89 (1.08, 3.29), respectively), as compared with those in the low exposure group (< 1.94 µg/g creatinine). This study demonstrates a potential relation between p-DCB exposure and prevalent endocrine-related reproductive cancers in US women. Prospective and mechanistic studies would further explore these interactions and elucidate the pathogenesis of endocrine-related female cancers potentially associated with p-DCB exposure.

Association of C-reactive protein gene polymorphisms with the risk of ischemic stroke: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The heterogeneous, complex condition known as ischemic stroke (IS) is brought on by the interaction of a number of risk factors and genetic variables. The association between C-reactive protein (CRP) gene polymorphisms and IS has, however, been the subject of inconsistent findings. Therefore, we conducted a meta-analysis to comprehensively address possible associations of CRP genes with the risk of IS. METHODS: A comprehensive literature search for all the published articles was performed in electronic databases including PubMed, EMBASE, Cochrane Library, and Google Scholar from January 1, 1950 to June 30, 2022. Odds ratio (OR) with 95% Confidence interval (CIs) along with fixed/random effect models were used to calculate summary estimates. RESULTS: Twelve case-control studies totalling 3880 IS cases and 5233 controls were included for the association of CRP gene polymorphisms (rs1800947, rs1130864, rs3093059, rs2794521, and rs1205). Across all genotyping models, we discovered that rs1130864, rs3093059, rs2794521, and rs1205SNPs were not substantially related to IS risk. A trend for significant association for rs1800947 under dominant (OR = 1.19; 95% CI = 0.97 to 1.48), recessive (OR = 1.49; 95% CI = 0.71 to 3.14) and allelic model (OR = 1.21; 95% CI = 0.99 to 1.48) was observed. However, protective association for rs1130864 under dominant (OR = 0.80; 95% CI = 0.70 to 0.91) and rs3093059 under allelic model (OR = 0.18; 95% CI = 0.14 to 0.22) was found. CONCLUSION: Our thorough study revealed that the CRP gene variants rs1800947, rs1130864, rs3093059, rs2794521, and rs1205 could not be related to the risk of ischemic stroke. However, additional research must focus on the rs1800947 polymorphisms in a particular group.

Exposure to endocrine-disrupting metals and serum estrogen levels among US women.

Multiple factors could affect estrogen levels in the body; however, the impact of exposure to endocrine-disrupting chemicals on estrogen levels in humans remains inconclusive. This cross-sectional study was to assess the association between blood levels of endocrine-disrupting metals (including cadmium, lead, and mercury) and serum estradiol levels in 1618 women (aged ≥ 20 years) who participated in the 2013-2016 National Health and Nutrition Examination Survey. Using multiple general linear models, we estimated percent changes of estradiol levels in association with blood metal concentrations. Age-specific analysis was further conducted. The median level of blood cadmium, lead, and mercury was 0.31 µg/L (range: 0.07-7.23), 0.76 µg/dL (0.11-12.80), and 0.73 µg/L (0.20-36.90), respectively, and the median estradiol level was 31.10 pg/mL (range: 2.12-523.00) among women aged 20-80 years. After adjusting for potential confounders, a 10 % increase in blood cadmium and lead levels was associated with 1.43 % (95 % CI: 0.50, 2.37) increased levels and 1.45 % (- 2.17, - 0.11) decreased levels of estrogen, respectively, in the total study population. When stratified by age, the positive association with cadmium was only seen in women aged 20-49 years [1.47 % (0.39, 2.56) increased estradiol] and the inverse association with lead was seen among women aged 50-80 years [3.40 % (- 4.78, - 2.00) decreased estradiol]. Mercury was not significantly associated with estrogen levels. Our study demonstrates a potential relationship between exposure to endocrine-disrupting cadmium and lead and serum estrogen levels in US women. Age-specific associations were observed. Prospective and mechanistic studies are warranted to further explore these interactions and the associated reproductive toxicities.

Urinary Concentrations of Endocrine-Disrupting Metals and Prevalent Breast Cancer in US Women.

The toxic metals cadmium, lead, and mercury are endocrine-disrupting agents that could produce estrogenic effects involving breast carcinogenesis. In this study, we further explored the relationship between exposure to these metals and prevalent breast cancer among female participants, aged 20 years or older, in the 2007-2016 National Health and Nutrition Examination Survey (NHANES). Exposure was determined by measuring urinary concentrations of metals using inductively coupled plasma mass spectrometry. Urine creatinine-corrected concentrations of metals were calculated for each study participant. Multivariate logistic regression models were constructed to examine the association between urinary metals and prevalent breast cancer, adjusting for potential confounders. Of the 3352 study participants, 106 had been diagnosed with breast cancer (weighted prevalence, 3.13%). The results show that women with breast cancer had significantly higher urinary concentrations of lead and cadmium (both p < 0.0001) than those without breast cancer. After adjusting for all the covariates included in the study, however, only urinary lead was shown to be significantly associated with increased prevalence of breast cancer, with an odds ratio of 2.95 (95% CI: 1.13, 7.70) in the highest quartile of urinary lead concentrations (≥ 0.71 µg/g creatinine) as compared with the lowest quartile. No statistically significant associations were observed between urine cadmium or mercury levels and breast cancer. This study demonstrates a potential association between lead exposure and prevalent breast cancer among US women. Prospective and mechanistic studies are warranted to further investigate this interaction and explore the role of lead in breast carcinogenesis.

Exposure to p-dichlorobenzene and serum α-Klotho levels among US participants in their middle and late adulthood.

P-dichlorobenzene (p-DCB) is a volatile compound commonly used as pest repellent and air deodorant in the home and public buildings, leading to a widespread exposure in indoor environments. There has been an increasing concern about its metabolic and endocrine effects. In this study, we explored the relation between p-DCB exposure and serum levels of soluble α-Klotho, an anti-aging hormone, in US adults. A nationally representative subsample of 1485 adults 40-79 ages in the 2013-2016 National Health and Nutrition Examination Survey was analyzed for the association between p-DCB exposure, measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), the major metabolite of p-DCB, and serum α-Klotho levels using multiple general linear models, adjusting for potential confounders. Age- and sex-specific analyses were further conducted. The weighted geometric mean of urinary 2,5-DCP was 2.43 µg/L and the weighted mean of serum α-Klotho was 831.97 pg/mL in the study participants during 2013-2016. After adjusting for potential confounders and urinary creatinine, urinary 2,5-DCP was significantly associated with decreased serum levels of α-Klotho (regression coefficient ß = -9.88; p = 0.0133) in the total study population. When age- and sex-specific analyses being conducted, a significantly inverse association was found in older adults aged 60-79 years (ß = -20.40; p = 0.0001) and in males (ß = -13.81; p = 0.0097), but not in the middle ages (40-59 years) and in females. The strongest association was observed in older (60-79 years) male participants, with a 25.43 pg/mL reduction of α-Klotho levels per 1-unit increase of 2,5-DCP concentrations (p = 0.0008). This is the first study demonstrating a relation between p-DCB exposure, measured as 2,5-DCP, and decreased α-Klotho levels in older males. Additional studies would further explore these interactions and elucidate the pathogenesis of the potential effects of p-DCB exposure on aging.

Design and evaluation of a multimodal balance training system.

OBJECTIVE: Current balance training systems are designed exclusively for one particular type of training and assessment. Additionally, they comprise monotonous training programs. Therefore, patients in different stages of rehabilitation must use different balance training models from different manufacturers, resulting in high treatment cost. Furthermore, large spaces are required to accommodate the balance training machines, and doctors and physiotherapists have to learn to operate multiple machines. We aimed to design a multimodal balance training and assessment system that can accommodate the assessment and training of static, dynamic, reactive and proactive balance to satisfy individual needs. METHODS: The difficulty associated with combining static, dynamic, reactive and proactive balance training in a single system was to use radial and circumferential driving mechanisms together with a clutch mechanism, whereby circumferential and radial drivers were installed in the base of the system to drive a compound foot plate system with interchangeable springs, in order to adjust stiffness using the clutch. Based on the kinematic equation, the influence of system parameters on the change of the body's center of gravity were evaluated. The parameters included the radial offset of the driving mechanism (r), circumferential angle of rotation (θ), height of the base of the balance training system (h), horizontal distance between the body's standing center of gravity and the center of the foot plate (R), thickness of the padding mat (ΔH) and inclination angle (α). RESULTS: The difficulties associated with combining static, dynamic, reactive and proactive balance training models in a single system were solved using radial and circumferential driving mechanisms together with a clutch mechanism. The foot plate can swing back and forth within ±20° around the X-axis, swing left and right within ±20° around the Y-axis, swing diagonally within ±20°, swing 360° around the Z-axis, and adjust the height along the Z-axis. Furthermore, the inclination angle α, circumferential angle of rotation θ, and speed (dα/dt and dθ/dt) of the system can be controlled in real time. CONCLUSION: The developed balance training system is suitable for patients in different stages of rehabilitation. By providing multiple functionalities, this system can ensure high use rates, reduce costs and save space.

Recurrent neural network based high-precision position compensation control of magnetic levitation system.

For improving the dynamic quality and steady-state performance, the hybrid controller based on recurrent neural network (RNN) is designed to implement the position control of the magnetic levitation ball system in this study. This hybrid controller consists of a baseline controller, an RNN identifier, and an RNN controller. In the hybrid controller, the baseline controller based on the control law of proportional-integral-derivative is firstly employed to provide the online learning sample and maintain the system stability at the early control phase. Then, the RNN identifier is trained online to learn the accurate inverse model of the controlled object. Next, the RNN controller shared the same structures and parameters with the RNN identifier is applied to add the precise compensation control quantity in real-time. Finally, the effectiveness and advancement of the proposed hybrid control strategy are comprehensively validated by the simulation and experimental tests of tracking step, square, sinusoidal, and trapezoidal signals. The results indicate that the RNN-based hybrid controller can obtain higher precision and faster adjustment than the comparison controllers and has strong anti-interference ability and robustness.

IL-27 improves adoptive CD8+ T cells' antitumor activity via enhancing cell survival and memory T cell differentiation.

IL-27 is an anti-inflammatory cytokine that triggers enhanced antitumor immunity, particularly cytotoxic T lymphocyte responses. In the present study, we sought to develop IL-27 into a therapeutic adjutant for adoptive T cell therapy using our well-established models. We have found that IL-27 directly improved the survival status and cytotoxicity of adoptive OT-1 CD8+ T cells in vitro and in vivo. Meanwhile, IL-27 treatment programs memory T cell differentiation in CD8+ T cells, characterized by upregulation of genes associated with T cell memory differentiation (T-bet, Eomes, Blimp1, and Ly6C). Additionally, we engineered the adoptive OT-1 CD8+ T cells to deliver IL-27. In mice, the established tumors treated with OT-1 CD8+ T-IL-27 were completely rejected, which demonstrated that IL-27 delivered via tumor antigen-specific T cells enhances adoptive T cells' cancer immunity. To our knowledge, this is the first application of CD8+ T cells as a vehicle to deliver IL-27 to treat tumors. Thus, this study demonstrates IL-27 is a feasible approach for enhancing CD8+ T cells' antitumor immunity and can be used as a therapeutic adjutant for T cell adoptive transfer to treat cancer.

IL-27 Induces CCL5 Production by T Lymphocytes, Which Contributes to Antitumor Activity.

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells including T lymphocytes. In this study, we demonstrate that IL-27 directly induces CCL5 production by T lymphocytes, particularly CD8+ T cells in vitro and in vivo. IL-27-induced CCL5 production is IL-27R-dependent. In CD4+ T cells, IL-27-induced CCL5 production was primarily dependent on Stat1 activation, whereas in CD8+ T cells, Stat1 deficiency does not abrogate CCL5 induction. A chromatin immunoprecipitation assay revealed that in the CCL5 promoter region, both putative Stat3 binding sites exhibit significant binding to Stat3, whereas only one out of four Stat1 binding sites displays moderate binding to Stat1. In tumor-bearing mice, IL-27 induced dramatic production of CCL5 in tumor-infiltrating T cells. IL-27-induced CCL5 appears to contribute to an IL-27-mediated antitumor effect. This is signified by diminished tumor inhibition in anti-CCL5- and IL-27-treated mice. Additionally, intratumor delivery of CCL5 mRNA using lipid nanoparticles significantly inhibited tumor growth. Thus, IL-27 induces robust CCL5 production by T cells, which contributes to antitumor activity.

Neural network compensation control of magnetic levitation ball position based on fuzzy inference.

Aiming at the problem of poor transient performance of the control system caused by the control uncertainty of the undertrained neural network, a neural network compensation control method based on fuzzy inference is proposed in this paper. The method includes three control substructures: fuzzy inference block, neural network control block and basic control block. The fuzzy inference block adaptively adjusts the neural network compensation control quantity according to the control error and the error rate of change, and adds a dynamic adjustment factor to ensure the control quality at the initial stage of network learning or at the moment of signal transition. The neural network control block is composed of an identifier and a controller with the same network structure. After the identifier learns the dynamic inverse model of the controlled object online, its training parameters are dynamically copied to the controller for real-time compensation control. The basic control block uses a traditional PID controller to provide online learning samples for the neural network control block. The simulation and experimental results of the position control of the magnetic levitation ball show that the proposed method significantly reduces the overshoot and settling time of the control system without sacrificing the steady-state accuracy of neural network compensation control, and has good transient and steady-state performance and strong robustness simultaneously.

Online MR evaluation of inter- and intra-fraction uterus motions and bladder volume changes during cervical cancer external beam radiotherapy.

PURPOSE/OBJECTIVE(S): The purpose of the study was to assess the uterus motions and bladder volume changes of fractional movements in cervical sites throughout the external beam radiotherapy (EBRT) treatment. MATERIALS/METHODS: A prospective online MR imaging tracking study was conducted in EBRT 43 patients with at least 4 scans during each treatment (before: ultrasound scan, MRI scan, CBCT scan, after: MRI scan) were included. In order to improve the treatment repeatability, each patient was instructed to empty the bladder and drink 500 ml water 1 h before CT simulation and each treatment. If the ultrasound scan result reached the CT simulation volume of bladder, the treatment began. Bladder was outlined on the T2 weighted axial sequence and CBCT image by the two observers to avoid the influence of contouring. The data of bladder volume and scanning time were accurately recorded. The bladder volumes, filling rates and uterus motion were retrospectively analyzed by MIM software. RESULTS: Inter-fraction variation of the bladder volume was significant (p < 0.0001). Intra-fraction mean increase of the bladder volume was modest (30 cc) but significant (p < 0.001). Both inter- and intra-fraction of the uterus motion were significant. The average time between the pre-and post-fraction MRI scans was 27.82 ± 7.12 min (range 10-55 min) for IMRT plans and 24.14 ± 5.86 min (range7-38 min) for VMAT plan. Average bladder filling rate was 3.43 ml/min. The bladder filling rate did not change significantly with the course of treatment, but the bladder was more intolerant. CONCLUSION: This is the most detailed assessment of intra-fraction and inter-fraction motion during EBRT for cervical cancer. Finally, this study will inform appropriate treatment margins for online adaptive radiotherapy. We suggest that at least one image scan is needed before the EBRT. The portable US scanner provides a quick but unreliable measurement of the bladder volume. There is a significant statistical difference between the results of ultrasonic scanning and that of image scanning.

Formulation Comprising Arsenic Trioxide and Dimercaprol Enhances Radiosensitivity of Pancreatic Cancer Xenografts.

OBJECTIVE: To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts. METHODS: Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays. RESULTS: Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups (P < 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) (P < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT. CONCLUSION: These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.