LX1 Targets Androgen Receptor Variants and AKR1C3 to overcome Therapy Resistance in Advanced Prostate Cancer.

The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate cancer. Here, we designed, synthesized, and characterized a class of LX compounds targeting both AR/AR variants and AKR1C3. Molecular docking indicated that LX compounds bound to the AKR1C3 active sites. LX1 blocked AKR1C3 enzymatic activity, suppressing the conversion of androstenedione into testosterone. LX compounds also reduced AR/AR-V7 expression and downregulated their target genes. In vitro, LX1 inhibited the growth of prostate cancer cells resistant to antiandrogens, including enzalutamide, abiraterone, apalutamide, and darolutamide. Treatment with LX1 in vivo significantly decreased tumor growth, lowered serum PSA levels, and reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 overcame resistance to enzalutamide treatment, and the combination of LX1 with enzalutamide further suppressed tumor growth. Collectively, the dual effect of LX1 in reducing intratumoral testosterone and AR signaling, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.

Use of regional anesthesia within a pediatric interventional radiology suite reduced periprocedural opioid use without delaying the overall workflow: a retrospective study.

BACKGROUND: Nerve block utility has been extensively described in the operating room, however, there is a paucity of evidence regarding blocks in the interventional radiology (IR) suite, with no studies examining its safety and efficacy in children. METHODS: A retrospective study was conducted at a single tertiary-care children's hospital to evaluate the analgesic utility of nerve blocks during IR-performed sclerotherapy for bone cysts, venous malformations, and lymphatic malformations. Lymphatic and venous malformations were combined for final analysis. Patients between January 2016 and September 2022 had their medical records reviewed for procedural data, postprocedural pain scores, and analgesic administration data. RESULTS: 309 patients were included in the final analysis. Opioids were required significantly less frequently intraprocedurally and postprocedurally across subgroups. The proportion of patients who received opioids during their hospital course was significant between block and non-block patients, respectively: bone cyst: 62.7% vs 100% (p<0.001); venous and lymphatic malformation: 65.7% vs 97.4% (p<0.001). Average maximum postanesthesia care unit (PACU) pain scores were significantly lower in bone cyst patients with no significant difference seen in pain scores among venous and lymphatic malformation patients. There were no reported nerve block-related complications. DISCUSSION: Nerve blocks demonstrated an opioid-sparing effect intraprocedurally and postprocedurally for all subgroups. Their use among bone cyst patients was associated with significant reductions in average maximum PACU pain scores. Nerve blocks may constitute an effective opioid-sparing component of multimodal analgesia in pediatric patients undergoing IR sclerosis procedures. Prospective data are needed to establish the optimal utility of nerve blocks in the IR setting.

Intra-articular injection of an extended-release flavopiridol formulation represents a potential alternative to other intra-articular medications for treating equine joint disease.

OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation. ANIMALS: 4 healthy horses without evidence of forelimb lameness. METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 µg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points. RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point. CLINICAL RELEVANCE: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.

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-46 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.

Insights into the Impact of Organizational Factors and Burnout on the Employees of a For-Profit Psychiatric Hospital during the Third Wave of the COVID-19 Pandemic.

In this paper, we provide insights into the interplay among the organizational, job, and attitudinal factors and employees' intentions to resign during the third wave of the COVID-19 pandemic at a mental health hospital. We point out shortcomings in the relationship dynamics between executive administration and operational staff and propose a pathway to develop more effective leadership frameworks to increase job satisfaction. We integrate qualitative data from case information and open-ended questions posed to employees at a mental health hospital and quantitative data from a small-scale survey (n = 19). We highlight that the ability to achieve objectives, work autonomy, burnout, affective commitment, distributive and procedural justice, and job satisfaction are critical in determining individuals' intentions to resign. Individuals identified disconnectedness and moral distress as critical aspects, while highlighting empathy, compassion, satisfaction, and confidence as pivotal elements. Mental healthcare settings could benefit from enhancing the staff's ability to achieve objectives, work autonomy, affective commitment, and both distributive and procedural justice. Addressing burnout and implementing measures to increase job satisfaction are equally vital. Efficiently restructuring dynamics between various leadership levels and staff can significantly improve employee retention.

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.

Poor Glycemic Control Is Associated With More Rapid Kidney Function Decline After the Onset of Diabetic Kidney Disease.

BACKGROUND: The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear. METHODS: The association between baseline glycated hemoglobin (HbA1c) and rates of estimated glomerular filtration rate (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial and 2378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of eGFR decline were also evaluated in PERL. RESULTS: A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (-0.87 and -0.27 mL/min/1.73 m2/year per Hba1c unit increment, P < .0001 and P = .0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (P for interaction <.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe rather than moderate albuminuria (+1.13 vs + 0.26 mL/min/1.73 m2/year, P = .01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline. CONCLUSION: In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of glomerular filtration rate decline after DKD onset, especially in persons with severe albuminuria.

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.

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.