The heparin-binding domain of VEGF165 directly binds to integrin αvß3 and VEGFR2/KDR D1: a potential mechanism of negative regulation of VEGF165 signaling by αvß3.

VEGF-A is a key cytokine in tumor angiogenesis and a major therapeutic target for cancer. VEGF165 is the predominant isoform of VEGF-A, and it is the most potent angiogenesis stimulant. VEGFR2/KDR domains 2 and 3 (D2D3) bind to the N-terminal domain (NTD, residues 1-110) of VEGF165. Since removal of the heparin-binding domain (HBD, residues 111-165) markedly reduced the mitogenic activity of the growth factor, it has been proposed that the HBD plays a critical role in the mitogenicity of VEGF165. Here, we report that αvß3 specifically bound to the isolated VEGF165 HBD but not to VEGF165 NTD. Based on docking simulation and mutagenesis, we identified several critical amino acid residues within the VEGF165 HBD required for αvß3 binding, i.e., Arg123, Arg124, Lys125, Lys140, Arg145, and Arg149. We discovered that VEGF165 HBD binds to the KDR domain 1 (D1) and identified that Arg123 and Arg124 are critical for KDR D1 binding by mutagenesis, indicating that the KDR D1-binding and αvß3-binding sites overlap in the HBD. Full-length VEGF165 mutant (R123A/R124A/K125A/K140A/R145A/R149A) defective in αvß3 and KDR D1 binding failed to induce ERK1/2 phosphorylation, integrin ß3 phosphorylation, and KDR phosphorylation and did not support proliferation of endothelial cells, although the mutation did not affect the KDR D2D3 interaction with VEGF165. Since ß3-knockout mice are known to show enhanced VEGF165 signaling, we propose that the binding of KDR D1 to the VEGF165 HBD and KDR D2D3 binding to the VEGF165 NTD are critically involved in the potent mitogenicity of VEGF165. We propose that binding competition between KDR and αvß3 to the VEGF165 HBD endows integrin αvß3 with regulatory properties to act as a negative regulator of VEGF165 signaling.

The Synergy of 177Lu-FAPI-046 with Tyrosine Kinase Inhibitor in a Sarcoma Patient-Derived Xenograft Mouse Model.

BACKGROUND: Given the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining 177Lu-FAPI-46 with Pazopanib against this malignancy. METHODS: Patient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the 177Lu-FAPI-46 monotherapy group, and the 177Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored. RESULTS: The microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group. CONCLUSION: This study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of 177Lu-FAPI-46 with Pazopanib.

Effectiveness of the Huddles in Improving the Patient Safety Attitudes Among Clinical Team Members.

BACKGROUND AND OBJECTIVES: Huddles among members of interdisciplinary medical teams involve short stand-up sessions and allow team members to focus on existing or emerging patient safety issues, thereby facilitating team communication. Hospital managers are able to recognize the current situation of the organization through patient safety attitudes, strengthen team members' awareness of patient safety, and improve the quality of health care. The purpose of this study was to determine the effects of huddles on improving team members' attitudes toward patient safety. METHODS: We used a quasi-experimental design and selected 2 adult wards with similar properties as the experimental and comparison groups by convenience sampling. Data collection was from December 1, 2021, to June 30, 2022, at a teaching hospital in central Taiwan. Team members of the ward performing huddles formed the experimental group, and they participated 2 times per week in 15-minute huddles from 8:15 to 8:30 am for a total of 4 weeks. The comparison group adopted the routine team care process. Both groups completed the Safety Attitudes Questionnaire during the pre- and post-tests of the study. RESULTS: The experimental group scored significantly higher in the post-test than in the pre-test in all aspects of safety attitudes, with the exception of stress recognition. These improved aspects were teamwork climate (76.47 ± 15.90 vs 83.29 ± 13.52, P < .001), safety climate (75.94 ± 16.14 vs 82.81 ± 13.74, P < .001), job satisfaction (74.34 ± 20.22 vs 84.40 ± 17.22, P <.001), perceptions of management (78.02 ± 19.99 vs 85.51 ± 15.97, P < .001), and working conditions (78.85 ± 17.87 vs 86.81 ± 14.74, P < .001). CONCLUSION: Through the huddles, clinical team members improved their understanding of different aspects of safety attitudes. Such a study provided ward units with real-time improvement and adjustment in terms of patient safety during their medical work processes with better patient safety.

County-scale dataset indicating the effects of disasters on crops in Taiwan from 2003 to 2022.

A lack of crop disaster datasets has limited the exploration of the influence of small-scale disasters on crops. Because disasters are often defined on the basis of human impact, disaster databases may underestimate the effect of disasters on crop production. Additionally, the resolution of such databases is insufficient for evaluating the effects of disasters on small areas. In this study, crop disaster and daily weather datasets covering the period from 2003 to 2022 in Taiwan were developed. Total 9,245 damage records from 233 observations of crop disasters were mined from the Report on Crop Production Loss Caused by Disasters of Taiwan. Daily weather data were collected from weather stations. Entire crop disaster information including multiple disasters, crops, and affected regions was stored in crop disaster dataset. All datasets were cleaned up and refined to enhance their quality, and characteristics such as disaster and crop classification were added to enhance the applicability of these datasets. These datasets can be used to determine the relationship between disaster type and crop production losses.

Imaging diabetic cardiomyopathy in a type 1 diabetic rat model using 18F-FEPPA PET.

OBJECTIVE: Diabetic patients often experience chronic inflammation and fibrosis in their cardiac tissues, highlighting the pressing need for the development of sensitive diagnostic methods for longitudinal assessment of diabetic cardiomyopathy. This study aims to evaluate the significance of an inflammatory marker known as translocator protein (TSPO) in a positron emission tomography (PET) protocol for longitudinally monitoring cardiac dysfunction in a diabetic animal model. Additionally, we compared the commonly used radiotracer, 18F-fluoro-2-deoxy-d-glucose (18F-FDG). METHODS: Fourteen 7-week-old female Sprague-Dawley rats were used in this study. Longitudinal PET experiments were conducted using 18F-N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide (18F-FEPPA) (n = 3), the TSPO radiotracer, and 18F-FDG (n = 3), both before and after the onset of diabetes. Histological and immunohistochemical staining assays were also conducted in both the control (n = 4) and diabetes (n = 4) groups. RESULTS: Results indicated a significant increase in cardiac tissue uptake of 18F-FEPPA after the onset of diabetes (P < 0.05), aligning with elevated TSPO levels observed in diabetic animals according to histological data. Conversely, the uptake of 18F-FDG in cardiac tissue significantly decreased after the onset of diabetes (P < 0.05). CONCLUSION: These findings suggest that 18F-FEPPA can function as a sensitive probe for detecting chronic inflammation and fibrosis in the cardiac tissues of diabetic animals.

Recent progress in unraveling cardiovascular complications associated with primary aldosteronism: a succinct review.

This comprehensive review offers a thorough exploration of recent advancements in our understanding of the intricate cardiovascular complications associated with Primary Aldosteronism (PA). PA encompasses a spectrum of conditions characterized by hypertension and excessive production of aldosterone operating independently of the renin-angiotensin system. Given its association with an elevated risk of cardiovascular and cerebrovascular complications, as well as a higher incidence of metabolic syndrome in comparison to individuals with essential hypertension (EH), an accurate diagnosis of PA is of paramount importance. This review delves into the intricate interplay between PA and cardiovascular health and focuses on the key pathophysiological mechanisms contributing to adverse cardiac outcomes. The impact of different treatment modalities on cardiovascular health is also examined, offering insights into potential therapeutic approaches. By highlighting the significance of recognizing PA as a significant contributor to cardiovascular morbidity, this review emphasizes the need for improved screening, early diagnosis, and tailored management strategies to both enhance patient care and mitigate the burden of cardiovascular diseases. The findings presented herein underscore the growing importance of PA in the context of cardiovascular medicine and emphasize the potential for translating these insights into targeted interventions to improve patient outcomes.

The role of confirmatory tests in the diagnosis of primary aldosteronism.

Confirmatory tests for diagnosis of primary aldosteronism (PA) play an important role in sparing patients with a false-positive aldosterone-to-renin ratio (ARR) screening test from undergoing invasive subtyping procedures. We recommend that patients with a positive ARR test should undergo at least one confirmatory test to confirm or exclude the diagnosis of PA before directly proceeding to subtype studies, except for patients with significant PA phenotypes, including spontaneous hypokalemia, plasma aldosterone concentration >20 ng/dL plus plasma renin activity below a detectable level. Although a gold standard confirmatory test has not been identified, we recommend that saline infusion test and captopril challenge test, which were widely used in Taiwan. Patients with PA have been reported to have a higher prevalence of concurrent autonomous cortisol secretion (ACS). ACS is a biochemical condition of mild cortisol overproduction from adrenal lesions, but without the typical clinical features of overt Cushing's syndrome. Concurrent ACS may result in incorrect interpretation of adrenal venous sampling (AVS) and may lead to adrenal insufficiency after adrenalectomy. We recommend screening for ACS in patients with PA scheduled for AVS examinations as well as for adrenalectomy. We recommend the 1-mg overnight dexamethasone suppression test as screening method to detect ACS.

Enhanced antitumour response of gold nanostar-mediated photothermal therapy in combination with immunotherapy in a mouse model of colon carcinoma.

OBJECTIVES: This study investigated the potential of combining PTT with dendritic cell (DC)-based immunotherapy and anti-PD-L1 immune checkpoint blockade (ICB) therapy against colorectal cancer and elucidated the underlying mechanisms. METHODS: The CT26 tumour-bearing mice were divided into seven treatment groups: control, atezolizumab (A), dendritic cells (DC), pAuNSs-mediated PTT (PTT), PTT combined with atezolizumab (PTT + A), PTT combined with dendritic cells (PTT + DC), and PTT combined with dendritic cells and atezolizumab (PTT + DC + A). Therapeutic efficacy was monitored. RESULTS: PTT upregulated most immune cell membrane receptor genes, including PD-L1, and downregulated genes associated with antigen presentation and T cell activation. Although the PTT + A and PTT + DC treatments showed partial tumour growth retardation, the combination of PTT with DCs and atezolizumab (PTT + DC + A) exhibited the most significant antitumour effect, with a complete remission rate of 50% and prolonged survival. On day 14, tumour samples from non-responsive mice revealed insufficient recruitment of T cells as the reason for uncured tumours. Notably, mice cured with PTT + DC and PTT + DC + A treatments showed no detectable lung nodules. CONCLUSION: This study demonstrated that the combination of PTT with DC-based immunotherapy and atezolizumab effectively overcomes the non-sensitive nature of CT26 tumours. These findings highlight the potential of this combination approach for colorectal cancer treatment.

Impacts of Huddle Intervention on the Patient Safety Culture of Medical Team Members in Medical Ward: One-Group Pretest-Posttest Design.

Objective: A huddle is a short, regular meetings to discuss existing or emerging patient safety issues. Hospital administrators can encourage healthcare staff to voluntarily examine the potential occurrence and severity of risks, thereby enhancing awareness of patient safety. The purpose of this study is to explore the effects of huddle intervention on patient safety culture among medical team members and related factors. Methods: We used a one-group pretest-posttest research design and convenience sampled 109 members of the general internal medicine ward team members from a medical center in central Taiwan. They participated 2 times per week in 15-min huddles from 08:15 to 08:30 in the morning, which lasted for a total of 4 weeks. The process was based on submitted ideas, approved ideas, research ideas and standardization, and data on the safety attitudes questionnaire (SAQ) were collected during the huddles' intervention pretest and posttest. Results: After the huddle intervention, we found significantly improved scores for safety attitude, teamwork climate (76.49±16.13 vs 83.26±13.39, p < 0.001), safety climate (75.07±16.07 vs 82.63±13.72, p < 0.001), job satisfaction (73.67±19.84 vs 83.39±17.21, p < 0.001), perceptions of management (77.87±19.99 vs 84.86±16.03, p < 0.001) and working conditions (78.96±18.16 vs 86.18±14.90, p < 0.001). Correlation analyses on the differences between pretest and posttest showed that age had a significant correlation with safety climate (r = 0.22, p = 0.022) and working conditions (r = 0.20, p = 0.035). The number of times to participate in a huddle had a significant correlation with teamwork climate (r = 0.33, p =<.001), safety climate (r = 0.30, p = 0.002), job satisfaction (r = 0.19, p = 0.043), and work conditions (r = 0.28, p = 0.003). Conclusion: Huddles improve clinical team members' understanding of different dimensions and relate factors of safety attitudes. Implementation of the huddles involved standardized process will help hospital administrators understand the steps to parallel expansion to other wards.

The heparin-binding domain of VEGF165 directly binds to integrin αvß3 and plays a critical role in signaling.

VEGF-A is a key cytokine in tumor angiogenesis and a major therapeutic target for cancer. VEGF165 is the predominant isoform and is the most potent angiogenesis stimulant. VEGFR2/KDR domains 2 and 3 (D2D3) bind to the N-terminal domain (NTD, residues 1-110) of VEGF165. Since removal of the heparin-binding domain (HBD, residues 111-165) markedly reduced the mitogenic activity of VEGF165, it has been proposed that the HBD plays a critical role in the mitogenicity of VEGF165. Integrin αvß3 has been shown to bind to VEGF165, but the role of integrin αvß3 in VEGF165 signaling are unclear. Here we describe that αvß3 specifically bound to the isolated HBD, but not to the NTD. We identified several critical amino acid residues in HBD for integrin binding (Arg-123, Arg-124, Lys-125, Lys-140, Arg-145, and Arg-149) by docking simulation and mutagenesis, and generated full-length VEGF165 that is defective in integrin binding by including mutations in the HBD. The full-length VEGF165 mutant defective in integrin binding (R123A/R124A/K125A/K140A/R145A/R149A) was defective in ERK1/2 phosphorylation, integrin ß3 phosphorylation, and KDR phosphorylation, although the mutation did not affect KDR binding to VEGF165. We propose a model in which VEGF165 induces KDR (through NTD)-VEGF165 (through HBD)-integrin αvß3 ternary complex formation on the cell surface and this process is critically involved in potent mitogenicity of VEGF165.

The effect of estrogen therapy on cerebral metabolism in diabetic female rats.

The impact of estrogen on brain function, especially in individuals with diabetes, remains uncertain. This study aims to compare cerebral glucose metabolism levels in intact rats, ovariectomized (OVX) rats, and 17ß-estradiol (E2)-treated OVX diabetic female rats. Sixteen rats were administered a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to induce diabetes (intact, n = 6; OVX, n = 6; OVX+E2-treated, n = 4). Additionally, 18 rats received an equivalent solvent dose via intraperitoneal injection (intact, n = 6; OVX, n = 6; OVX+E2-treated, n = 6). After 4 weeks of STZ or solvent administration, positron emission tomography scans with 18F-fluorodeoxyglucose (18F-FDG) injection were employed to assess cerebral glucose metabolism. The diabetic rats exhibited substantial reductions in 18F-FDG uptake across all brain regions (all P < 0.01), in contrast to the control rats. Moreover, intact and OVX + E2-treated diabetic female rats displayed more pronounced decreases in cerebral glucose metabolism in the amygdala and hippocampus compared to OVX diabetic female rats (P < 0.05). These findings suggest that diabetes creates an environment wherein estrogen exacerbates neuropathology and intensifies neuronal activity.

Improvement of composite kidney outcomes by AKI care bundles: a systematic review and meta-analysis.

INTRODUCTION: Various approaches have been suggested to identify acute kidney injury (AKI) early and to initiate kidney-protective measures in patients at risk or with AKI. The objective of this study was to evaluate whether care bundles improve kidney outcomes in these patients. METHODS: We conducted a systematic review of the literature to evaluate the clinical effectiveness of AKI care bundles with or without urinary biomarkers in the recognition and management of AKI. The main outcomes were major adverse kidney events (MAKEs) consisting of moderate-severe AKI, receipt of renal replacement therapy (RRT), and mortality. RESULTS: Out of 7434 abstracts screened, 946 published studies were identified. Thirteen studies [five randomized controlled trials (RCTs) and eight non-RCTs] including 16,540 patients were eligible for inclusion in the meta-analysis. Meta-analysis showed a lower incidence of MAKE in the AKI care bundle group [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.66-0.81] with differences in all 3 individual outcomes [moderate-severe AKI (OR 0.65, 95% CI 0.51-0.82), RRT (OR 0.63, 95% CI = 0.46-0.88) and mortality]. Subgroup analysis of the RCTs, all adopted biomarker-based approach, decreased the risk of MAKE (OR 0.55, 95% CI 0.41-0.74). Network meta-analysis could reveal that the incorporation of biomarkers in care bundles carried a significantly lower risk of MAKE when compared to care bundles without biomarkers (OR = 0.693, 95% CI = 0.50-0.96), while the usual care subgroup had a significantly higher risk (OR = 1.29, 95% CI = 1.09-1.52). CONCLUSION: Our meta-analysis demonstrated that care bundles decreased the risk of MAKE, moderate-severe AKI and need for RRT in AKI patients. Moreover, the inclusion of biomarkers in care bundles had a greater impact than care bundles without biomarkers.

A CSF-1R-blocking antibody/IL-10 fusion protein increases anti-tumor immunity by effectuating tumor-resident CD8+ T cells.

Strategies to increase intratumoral concentrations of an anticancer agent are desirable to optimize its therapeutic potential when said agent is efficacious primarily within a tumor but also have significant systemic side effects. Here, we generate a bifunctional protein by fusing interleukin-10 (IL-10) to a colony-stimulating factor-1 receptor (CSF-1R)-blocking antibody. The fusion protein demonstrates significant antitumor activity in multiple cancer models, especially head and neck cancer. Moreover, this bifunctional protein not only leads to the anticipated reduction in tumor-associated macrophages but also triggers proliferation, activation, and metabolic reprogramming of CD8+ T cells. Furthermore, it extends the clonotype diversity of tumor-infiltrated T cells and shifts the tumor microenvironment (TME) to an immune-active state. This study suggests an efficient strategy for designing immunotherapeutic agents by fusing a potent immunostimulatory molecule to an antibody targeting TME-enriched factors.

Association of urinary liver-type fatty acid-binding protein with outcomes after adrenalectomy for unilateral primary aldosteronism.

BACKGROUND AND AIMS: This study explored the association between urinary liver-type fatty acid-binding protein to creatinine (uL-FABP-cre) ratio and postoperative clinical failure in unilateral primary aldosteronism (PA) patients undergoing adrenalectomy. MATERIALS AND METHODS: Data from the Taiwan Primary Aldosteronism Investigation Group database were analyzed, including patients with unilateral PA who had adrenalectomy between December 2015 and October 2018. Statistical methods included generalized additive modeling, logistic regression analysis, net reclassification improvement (NRI), and the C statistic. RESULTS: In the study cohort of 131 patients (mean age 52.3 ± 10.8 years; 43.5% male), 117 achieved clinical success, while 14 experienced clinical failure. A uL-FABP-cre ratio ≥5 predicted clinical failure (odds ratio: 6.22, p = 0.005). Subgroup analysis revealed its efficacy in predicting clinical failure in patients with BMI ≥ 24 kg/m2, normokalemia, or <5 years of hypertension. Furthermore, incorporating uL-FABP-cre ratio into the Primary Aldosteronism Surgical Outcome (PASO) score significantly improved predictive ability. The addition increased the C statistic from 0.671 to 0.762 (p < 0.01) and improved category-free NRI by 0.675 (p = 0.014). CONCLUSION: A uL-FABP-cre ratio ≥5 accurately predicted clinical failure post-adrenalectomy in unilateral PA, enhancing PASO score's identification of high-risk patients for postoperative clinical failure.

Brain alterations in ovariohysterectomized rats revealed by diffusion tensor imaging.

OBJECTIVES: Women undergoing hysterectomy with oophorectomy have an increased risk of Alzheimer's disease and Parkinson's disease. However, postoperative neuroimaging data on pathogenic processes in the brain are limited. The aim of this study was to investigate the potential effect of ovariohysterectomy on brain integrity in rat model using diffusion tensor imaging (DTI) technique for the first time. METHODS: We enrolled 13 rats each in the control and ovariohysterectomy groups. Rats in the ovariohysterectomy group underwent the ovariohysterectomy at 7 weeks of age, and all rats underwent DTI scans at 9 weeks of age. The DTI-derived parameters, such as fractional anisotropy and mean diffusivity, were compared between the control and ovariohysterectomy groups. RESULTS: Compared to the control group, the ovariohysterectomy group showed significantly lower fractional anisotropy in various brain regions, including the corpus callosum, bilateral striatum, and bilateral cortex (all P  < 0.05), suggesting neuronal injury in ovariohysterectomized rats. Mean diffusivity did not differ significantly between groups (all P  > 0.05). CONCLUSION: Rats undergoing ovariohysterectomy had lower fractional anisotropy compared to control in widespread brain regions, suggesting neuronal injury and demyelination. Therefore, neuroimaging should be performed to monitor brain alterations in women after hysterectomy with bilateral oophorectomy in clinical settings.

Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy.

Antibodies conjugated with diagnostic/therapeutic radionuclides are attractive options for inoperable cancers lacking accurate imaging methods and effective therapeutics, such as pancreatic cancer. Hence, we have produced an antibody radionuclide conjugate termed TE-1132 comprising a α-CA19-9 scFv-Fc that is site-specifically conjugated at each C-terminus to 3 DOTA chelators via a cysteine-containing peptide linker. The smaller scFv-Fc size facilitates diffusivity within solid tumors, whereas the chelator-to-antibody ratio of six enabled 177Lu-radiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [111In]In-TE-1132 and the biodistribution of [177Lu]Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [177Lu]Lu-TE-1132 effectively inhibited the BxPC3 tumor growth and prolonged the survival of mice with no irreversible body weight loss or hematopoietic damage. The adequate pharmacokinetic parameters, prominent tumor accumulation, and efficacy with good safety in mice encourage the further investigation of theranostic TE-1132 for treating pancreatic cancer.

4D-printed needle panel meters coupled with enzymatic derivatization for reading urea and glucose concentrations in biological samples.

On-site analytical techniques continue being developed with advances in modern technology. To demonstrate the applicability of four-dimensional printing (4DP) technologies in the direct fabrication of stimuli-responsive analytical devices for on-site determination of urea and glucose, we used digital light processing three-dimensional printing (3DP) and 2-carboxyethyl acrylate (CEA)-incorporated photocurable resins to fabricate all-in-one needle panel meters. When adding a sample having a value of pH above the pKa of CEA (ca. 4.6-5.0) into the fabricated needle panel meter, the [H+]-responsive layer of the needle, printed using the CEA-incorporated photocurable resins, swelled as a result of electrostatic repulsion among the dissociated carboxyl groups of the copolymer, leading to [H+]-dependent bending of the needle. When coupled with a derivatization reaction (urease-mediated hydrolysis of urea to decrease [H+]; glucose oxidase-mediated oxidization of glucose to increase [H+]), the bending of the needle allowed reliable quantification of urea or glucose when referencing pre-calibrated concentration scales. After method optimization, the method's detection limits for urea and glucose were 4.9 and 7.0 µM, respectively, within a working concentration range from 0.1 to 10 mM. We verified the reliability of this analytical method by determining the concentrations of urea and glucose in samples of human urine, fetal bovine serum, and rat plasma with spike analyses and comparing the results with those obtained using commercial assay kits. Our results confirm that 4DP technologies can allow the direct fabrication of stimuli-responsive devices for quantitative chemical analysis, and that they can advance the development and applicability of 3DP-enabling analytical methods.

Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator.

Radiotherapy (RT) is an effective cancer treatment. The abscopal effect, referring to the unexpected shrinkage observed in non-irradiated tumors after radiation therapy, is thought to be mediated by systemic immune activation. However, it has low incidence and is unpredictable. Here, RT was combined with curcumin to investigate how curcumin affects RT-induced abscopal effects in mice with bilateral CT26 colorectal tumors. Indium 111-labeled DOTA-anti-OX40 mAb was synthesized to detect the activated T cell accumulations in primary and secondary tumors correlating with the changes in protein expressions and tumor growth to understand the overall effects of the combination of RT and curcumin. The combination treatment caused the most significant tumor suppression in both primary and secondary tumors, accompanied by the highest 111In-DOTA-OX40 mAb tumor accumulations. The combination treatment elevated expressions of proapoptotic proteins (Bax and cleaved caspase-3) and proinflammatory proteins (granzyme B, IL-6, and IL-1ß) in both primary and secondary tumors. Based on the biodistribution of 111In-DOTA-OX40 mAb, tumor growth inhibition, and anti-tumor protein expression, our findings suggest that curcumin could act as an immune booster to augment RT-induced anti-tumor and abscopal effects effectively.

Tolerability and pharmacokinetics of intravenous allopregnanolone with and without midazolam pretreatment in two healthy dogs.

The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here, we assess the cardiopulmonary safety of intravenous ALLO by itself and after a clinically recommended dose of midazolam (MDZ) in two healthy adult beagles. Each dog received ALLO (1 mg/kg, IV), and after a washout period of 2 weeks, each dog was dosed with MDZ (0.2 mg/kg, IV) followed 10 minutes later by ALLO. Behavioral state, vital signs, arterial blood gases, blood chemistries, and plasma ALLO concentrations were monitored for up to 6 hours after dosing. The dogs appeared sleepy but were fully responsive after both treatments. No depression of mean arterial pressure or respiratory rate was noted. Blood gas measurements failed to show evidence of drug-induced acute respiratory acidosis. Estimated maximum plasma ALLO concentrations were in the range of 1500 to 3000 ng/ml. The results indicate that intravenous ALLO can be used safely to treat benzodiazepine-refractory SE, even when administered shortly after a benzodiazepine.

Comparison of the synthesis and biological properties of no-carrier-added and carrier-added 4-borono-2-[18F]fluorophenylalanine ([18F]FBPA).

PURPOSE: Boron neutron capture therapy (BNCT), an attractive strategy for cancer treatment, can kill tumor cells and avoid injury to surrounding healthy cells. 4-Borono-2-[18F]fluorophenylalanine ([18F]FBPA) positron emission tomography (PET) is a reliable tool for patient screening. Due to the relatively low radiochemical yield when employing the electrophilic route, this study was able to develop a new method to produce no-carrier-added (NCA) [18F]FBPA and compare the biological characteristics with carrier-added (CA) characteristics. PROCEDURES: By starting from 4-bromo-2-nitrobenzaldehyde, NCA [18F]FBPA was prepared using radiofluorination, alkylation, borylation, and hydrolysis. Cellular uptake analyses, microPET imaging, and biodistribution analyses were conducted to characterize the biological properties of NCA and CA [18F]FBPA. RESULTS: The radiochemical yield of NCA [18F]FBPA was 20 % ± 6 % (decay corrected) with a radiochemical purity of >98 % and molar activity of 56 ± 15 GBq/µmol in a 100-min synthesis. The in vitro accumulation was significantly higher for NCA [18F]FBPA than for CA [18F]FBPA in both SAS and CT-26 cells. However, no apparent differences in tumor uptake were observed between NCA and CA [18F]FBPA-injected tumor-bearing mice. CONCLUSIONS: We successfully prepared NCA [18F]FBPA through nucleophilic substitution and achieved improved radiochemical yield and purity. We also demonstrated the effects of the amount of nonradioactive FBPA on in vitro cellular uptake and in vivo imaging studies.