Synergistic anticancer immunity in metastatic triple-negative breast cancer through an in situ amplifying Peptide-Drug Conjugate.

Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvß3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a 'hot' tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies.

Rationally Designed Li-Ag Alloy with In-Situ-Formed Solid Electrolyte Interphase for All-Solid-State Lithium Batteries.

All-solid-state lithium batteries (ASSLBs) with sulfide-based solid electrolytes have attracted significant attention as promising energy storage devices, owing to their high energy density and enhanced safety. However, the combination of a lithium metal anode and a sulfide solid electrolyte results in performance degradation, owing to lithium dendrite growth and the side reactions of lithium metal with the solid electrolyte. To address these issues, a Ag-based Li alloy with a favorable solid electrolyte interphase (SEI) was prepared using electrodeposition and applied to the ASSLB as an anode. The electrochemically formed SEI layer on the Li-Ag alloy primarily comprised LiF and Li2O with high mechanical strength and Li3N with high ionic conductivity, which suppressed the formation of lithium dendrites and short-circuiting of the cell. The symmetric cell with the Li-Ag alloy achieved a critical current density of 1.6 mA cm-2 and maintained stable cycling for over 2000 h at a current density of 0.6 mA cm-2. Consequently, the all-solid-state lithium cell assembled with the Li-Ag alloy anode with SEI, Li6PS5Cl solid electrolyte, and LiNi0.78Co0.10Mn0.12O2 cathode delivered a high discharge capacity of 185 mAh g-1 and exhibited good cycling performance in terms of cycling stability and rate capability at 25 °C.

Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer.

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway.

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

Machine learning-based response assessment in patients with rectal cancer after neoadjuvant chemoradiotherapy: radiomics analysis for assessing tumor regression grade using T2-weighted magnetic resonance images.

PURPOSE: This study aimed to assess tumor regression grade (TRG) in patients with rectal cancer after neoadjuvant chemoradiotherapy (NCRT) through a machine learning-based radiomics analysis using baseline T2-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: In total, 148 patients with locally advanced rectal cancer(T2-4 or N+) who underwent MR imaging at baseline and after chemoradiotherapy between January 2010 and May 2021 were included. A region of interest for each tumor mass was drawn by a radiologist on oblique axial T2-weighted images, and main features were selected using principal component analysis after dimension reduction among 116 radiomics and three clinical features. Among eight learning models that were used for prediction model development, the model showing best performance was selected. Treatment responses were classified as either good or poor based on the MR-assessed TRG (mrTRG) and pathologic TRG (pTRG). The model performance was assessed using the area under the receiver operating curve (AUROC) to classify the response group. RESULTS: Approximately 49% of the patients were in the good response (GR) group based on mrTRG (73/148) and 26.9% based on pTRG (28/104). The AUCs of clinical data, radiomics models, and combined radiomics with clinical data model for predicting mrTRG were 0.80 (95% confidence interval [CI] 0.73, 0.87), 0.74 (95% CI 0.66, 0.81), and 0.75(95% CI 0.68, 0.82), and those for predicting pTRG was 0.62 (95% CI 0.52, 0.71), 0.74 (95% CI 0.65, 0.82), and 0.79 (95% CI 0.71, 0.87). CONCLUSION: Radiomics combined with clinical data model using baseline T2-weighted MR images demonstrated feasible diagnostic performance in predicting both MR-assessed and pathologic treatment response in patients with rectal cancer after NCRT.

Comparison of Four Diagnostic Guidelines for Hepatocellular Carcinoma Using Gadoxetic Acid-enhanced Liver MRI.

Background Noninvasive diagnostic guidelines for hepatocellular carcinoma (HCC) vary across different global geographic areas, especially regarding criteria about gadoxetic acid-enhanced MRI. Purpose To compare the diagnostic performance of four different international HCC diagnosis guidelines and readers' judgment in diagnosing HCC using gadoxetic acid-enhanced MRI in patients at high risk for HCC. Materials and Methods This retrospective study included patients who had not undergone treatment, were at risk for HCC, and who underwent gadoxetic acid-enhanced MRI from January 2015 to June 2018 from 11 tertiary hospitals in South Korea. Four radiologists independently reviewed focal liver lesions (FLLs) according to four guidelines: American Association for the Study of Liver Diseases (AASLD)/Liver Imaging Reporting and Data System (LI-RADS), Korean Liver Cancer Association-National Cancer Center (KLCA-NCC), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL). Reader judgment (HCC or not HCC) was also recorded. Malignant FLLs were confirmed at pathology, and histologic and clinical follow-up data were used for benign FLLs. The guidelines' diagnostic performance was compared using generalized estimating equations. Additionally, the diagnostic odds ratio was assessed. Results A total of 2445 FLLs (median size, 27.4 mm) were analyzed in 2237 patients (mean age, 59 years ± 11 [SD]; 1666 male patients); 69.3% (1694 of 2445) were HCCs. KLCA-NCC showed the highest accuracy (80.0%; 95% CI: 78.7, 81.2; P = .001), with high sensitivity in Eastern guidelines (APASL, 89.1% [95% CI: 87.8, 90.3]; KLCA-NCC, 78.2% [95% CI: 76.6, 79.7]) and high specificity in Western guidelines (AASLD/LI-RADS, 89.6% [95% CI: 87.8, 91.2]; EASL, 88.1% [95% CI: 86.2, 89.9]) (P = .001). The diagnostic odds ratios were 20.7 (95% CI: 17.0, 25.3) for AASLD/LI-RADS, 18.9 (95% CI: 15.8, 22.6) for KLCA-NCC, 16.8 (95% CI: 13.8, 20.4) for EASL, and 8.9 (95% CI: 7.4, 10.7) for APASL. The readers' judgment demonstrated higher accuracy than that of the guidelines (accuracy, 86.0%; 95% CI: 84.9, 86.9; P = .001). Conclusion Among four different international HCC diagnosis guidelines, Eastern guidelines demonstrated higher sensitivity, whereas Western guidelines displayed higher specificity. KLCA-NCC achieved the highest accuracy, and AASLD/LI-RADS exhibited the highest diagnostic odds ratio. © RSNA, 2024 Supplemental material is available for this article.

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract.

Background: For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog's poor cellular permeability and gastrointestinal (GI) stability. Methods: To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic (db/db) mouse model were evaluated. Results: The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10-6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion: The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.

Net global warming potential index rather than soil carbon stock change could provide better understanding of the carbon balance in soil systems.

This study was conducted to determine the soil organic carbon (SOC) stock change factor for green manure crops that was developed by the Intergovernmental Panel on Climate Change (IPCC) Tier 2 method and compare this with the net global warming potential (GWP) index that is used to evaluate the contribution of green manuring to global warming. Four treatments were barley (Hordeum vulgare L.; B), hairy vetch (Vicia villosa R.; HV), a barley/hairy vetch mixture (BHV) and a conventional treatment (C). The aboveground biomass of green manure crops was incorporated into the soil on 25 May 2018, 26 April 2019, 29 April 2020, 30 April 2021 and 2 May 2022. Maize (Zea mays L.) was transplanted as the subsequent crop after the incorporation of green manures. SOC stock decreased with green manures, even though carbon input with green manures, including B, HV and BHV, was greater than that with C. The mean value of the SOC stock change factor for green manure crops, including B, HV and BHV was 0.627 and was significantly lower than that of the C. However, the net GWP also decreased with the incorporation of green manure crops, and the mean value of the relative net GWP index across B, HV and BHV was 0.853. These conflicting results were caused by different estimation methods between annual SOC change (△SOC) and net GWP. The estimation of SOC stock change using △SOC suggested by the IPCC method may overestimate the contribution of green manure crops to global warming. The net GWP method with comprehensive input and output of carbon in the soil system could provide a better understanding of the carbon balance in soil systems. In the current study, the comparison of △SOC and net GWP was conducted for at one site of upland soil for 5 years. Therefore, further research on estimating the effect of green manure crops on net GWP in various types of soil for longer years should be conducted.

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

BACKGROUND: Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). METHODS: In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. RESULTS: In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 µg/kg) lowered the glucose level more than bD-G1A (50 µg/kg) compared with the control (35.5% vs. 26.4%). CONCLUSION: GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment.

Typical MR features and interpretation of perianal fistulas in patients with Crohn's disease.

Perianal fistulas in Crohn's disease (CD) are a poor prognostic phenotype requiring a combination of medical and surgical management. Perianal fistulas in CD are characterized by more complex and multi-branched fistulas, association with skin tags, and frequent presence of proctitis. A comprehensive approach with clinical examination, endoscopic and MR assessment is required, and in particular, MR interpretation provides detailed information on the type of fistula with its internal component and activity, secondary tracts and extension, internal, external openings, associated abscess, and presence of proctitis. Structured reporting of these items would be recommended for further discussion and management planning both at initial diagnosis and for disease monitoring during treatment follow-up. Management strategy would be individualized for each patient, and control of luminal disease activity could be an important determinant in the selection of treatment options. In this review, we provide an overview of the MRI evaluation of perianal fistulas in CD with a proposed structured MR report.

Assessing Active Bowel Inflammation in Crohn's Disease Using Intestinal Ultrasound: Correlation With Fecal Calprotectin.

AIM: To analyze the correlation between intestinal ultrasound (IUS) and serum and fecal biomarkers, and the characteristics of small bowel disease, for the assessment of active bowel inflammation. METHODS: Patients with Crohn's disease (CD) who underwent an initial IUS examination between July 2018 and November 2022 at our institution were included retrospectively. We divided small and large bowels into seven segments, and recorded the presence of active inflammation according to following criteria: bowel wall thickness ≥ mm with ≥1 of feature of active disease on IUS. The correlations between IUS-assessed activity and serum C-reactive protein (CRP, mg/dL) and fecal calprotectin (FC, µg/g) levels were analyzed. RESULTS: A total of 127 patients were included (mean age: 32.42 ± 12.07, M:F = 90:37, median disease duration 6 years [0-35]). Of them, 78 showed active bowel inflammation (61.4%), with inflammation distal to the terminal ileum being the most common disease location (n = 61, 78.2%). FC and serum CRP levels were significantly correlated with the number of segments with active inflammation (rho = 0.58, 0.48), number of segments with complications (r = 0.35, 0.31), and US activity score (r = 0.62, 0.54). With FC cutoff values of 100 and 150 µg/g, the concordance rates for patients with active small bowel disease were 78.7% (26/33) and 72.7% (24/33), respectively, which were better than those for other disease locations. CONCLUSIONS: Disease activity determined by IUS was significantly correlated with the biomarkers, with a better concordance rate in patients with active small bowel disease than in those with other disease locations with FC cut-off values of 100 and 150 µg/g.

Accelerometer-derived physical activity analysis of elderly osteoarthritis patients.

BACKGROUND: Because disability in Osteoarthritis (OA) may change physical activity (PA), which might affect the disease progression, it is important to measure a patient's daily PA to study the relationship between a patient's PA and disease progression. OBJECTIVE: The objective of the present study was to investigate the relationship between PA and patients with OA and people without OA using data from the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: Demographic study was conducted to obtain data of comorbidities of participants. PA was compared between the group with OA (OA group) and the group without OA (non-OA group). In addition, PAs of OA patients with comorbidities and those without comorbidities were compared. The cut-off of moderate to vigorous physical activity (MVPA) was obtained through a receiver operating characteristic (ROC) curve. RESULTS: In the demographic study, there were significantly more educated participants in the OA group (p < .001). Actigraph data showed a significant decrease in MVPA (p < .001) but a significant increase in light activity (p = .002) in the OA group. In addition, the OA group showed significantly lower light PA but significantly higher MVPA in ≥10 min bout length. OA patients with comorbidities showed higher MVPA than OA patients without comorbidities (p = .044). The cut-off point of MVPA was 7.071 min/day when ROC curve was conducted. CONCLUSIONS: The present study suggests that patients with OA and low activity need a certain level of physical activity and a cut-off point for MVPA is presented which accounts for comorbidities in OA patients.

Correlation between Harris hip score and gait analysis through artificial intelligence pose estimation in patients after total hip arthroplasty.

BACKGROUND: Recently, open pose estimation using artificial intelligence (AI) has enabled the analysis of time series of human movements through digital video inputs. Analyzing a person's actual movement as a digitized image would give objectivity in evaluating a person's physical function. In the present study, we investigated the relationship of AI camera-based open pose estimation with Harris Hip Score (HHS) developed for patient-reported outcome (PRO) of hip joint function. METHOD: HHS evaluation and pose estimation using AI camera were performed for a total of 56 patients after total hip arthroplasty in Gyeongsang National University Hospital. Joint angles and gait parameters were analyzed by extracting joint points from time-series data of the patient's movements. A total of 65 parameters were from raw data of the lower extremity. Principal component analysis (PCA) was used to find main parameters. K-means cluster, X-squared test, Random forest, and mean decrease Gini (MDG) graph were also applied. RESULTS: The train model showed 75% prediction accuracy and the test model showed 81.8% reality prediction accuracy in Random forest. "Anklerang_max", "kneeankle_diff", and "anklerang_rl" showed the top 3 Gini importance score in the Mean Decrease Gini (MDG) graph. CONCLUSION: The present study shows that pose estimation data using AI camera is related to HHS by presenting associated gait parameters. In addition, our results suggest that ankle angle associated parameters could be key factors of gait analysis in patients who undergo total hip arthroplasty.

Related Factors for Unfavorable Disease Course in Patients with Crohn's Disease: An Observational Retrospective Study.

Background: Crohn's disease (CD) manifests a heterogeneous clinical spectrum and disease course, and it is challenging to predict the disease outcome based on initial presentation. Objective: To analyze the long-term disease course and factors leading to poor prognosis of CD. Methods: In total, 112 patients with CD who were initially diagnosed and treated at our institution from January 2009 to August 2020 were included. We analyzed their clinical data, disease characteristics according to the Montreal classification, and the endoscopic and computed tomography (CT) examinations at the initial visit and at 2-year, 5-year, and last follow ups. We categorized the disease course into the following four categories: remission, stable, chronic refractory, and chronic relapsing. Significant factors associated with a poorer prognosis were analyzed. Results: The median follow-up period was 107 (range, 61−139) months. Complicated disease behavior increased slightly over the follow-up period (20.5% to 26.2%). An unfavorable disease course was defined as chronic refractory (19.6%) and relapsing (16.1%) courses. The 2-year disease characteristics were significant factors for unfavorable disease course, and the combination of 2-year perianal disease and 2-year moderate-to-severe CT activity could predict unfavorable disease course with the highest accuracy (0.722; area under the curve: 0.768; p < 0.0001). Conclusions: One-third of the patients with CD showed an unfavorable disease course (35.7%), and 2-year disease characteristics were significant factors for an unfavorable disease course.

Serial Changes in Body Composition and the Association with Disease Activity during Treatment in Patients with Crohn's Disease.

Objectives: To analyze serial changes in body composition and investigate the association between body composition changes and disease activity changes in patients with Crohn's disease (CD). Methods: Seventy-one patients with CD who had been treated and followed-up at our institution were included. Two to four computed tomography images were acquired at baseline, and the 2−5-year, 5−8-year, and last follow-ups were selected per patient for body composition and disease activity analyses. Visceral fat area (VFA), skeletal muscle index (SMI; skeletal muscle area/height2), and subcutaneous fat area (SFA) were assessed using an artificial-intelligence-driven fully automated method. Disease activity was assessed using a modified computed tomography scoring system and the Simple Endoscopic Score for Crohn's Disease. The associations between body composition, disease activity, and remission were investigated. Results: The mean age was 29.83 ± 11.27 years; most patients were men (48/71, 67.6%); and the median follow-up was 144 (12−264) months. Overall, VFA and SFA gradually increased, while SMI decreased during the follow-up. Sarcopenia was associated with the female sex, higher disease activities at baseline (p = 0.01) and the last follow-up (p = 0.001). SMI and SFA inversely correlated with the disease activity, i.e., the more severe the disease activity, the lower the SMI and SFA (p < 0.05). SMI at the last follow-up was the only significant predictor of remission (OR = 1.21, 95% confidence interval: 1.03−1.42, p = 0.021). Conclusion: SMI decreased while VFA and SFA increased during the treatment follow-up in patients with CD. Sarcopenia was associated with higher disease activity, and SMI and SFA inversely correlated with disease activity. SMI at the last follow-up was the significant factor for remission.

Botulinum toxin injection strategy of intractable and relapsed piriformis syndrome: A case report.

RATIONALE: Piriformis syndrome (PS) is neuromuscular disorder caused by sciatic nerve compression by piriformis muscle and related to sciatic-type pain. When the conservative care fails, local injection or surgery can be also performed into piriformis. In recent years, botulinum toxin (BoNT) has also been considered as a new therapeutic option of piriformis syndrome. PATIENT CONCERNS: A man in his late 40s came to pain clinic for left low back pain. The symptom was aggravated with sitting position. DIAGNOSIS: Piriformis syndrome. INTERVENTIONS: The patient underwent BoNT injection with 100 IU with 2 mL into piriformis muscle for piriformis syndrome treatment, and his pain was relieved. However, it recurred 8 months later. BoNT injection was repeated with 100 IU with 5 mL. OUTCOMES: At the time of this writing, his pain was reduced for 2 years without any medication. LESSONS: We report a case of treating relapsed piriformis syndrome with BoNT injection of different dilution volume, suggesting that the higher the dilution volume, the more effective for therapeutic effect of BoNT.

COMPARISON OF GAMMA ABSORBED DOSE RATES IN THE AIR MEASURED WITH A PORTABLE SURVEY METER AND THE SOIL RADIOACTIVITY MEASUREMENTS.

To compare the measurement results of a portable survey meter with a soil-based dose rate assessment method, the gamma absorbed dose rates in the air were measured at 27 sites. The soil-based gamma absorbed dose rates in the air were calculated using established conversion factors and the activity concentrations of 226Ra, 232Th and 40K of the soil at the sites. The gamma absorbed dose rate averages of the portable survey meter, and computing from the activity concentrations in the soil were 65.8 ± 4.26 and 64.8 ± 3.68 nGy⋅h-1, respectively. A significant positive correlation was found in the comparison between the evaluated gamma absorbed dose rates from soil radioactivity and in the air. Conversion factors based on the local soils converting to the absorbed dose rate were computed from the portable survey meter data and the soil activity concentrations, and it was compared with others.

Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer.

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.

Comparison of Diagnostic Performance of Ultrasonography and Magnetic Resonance Enterography in the Assessment of Active Bowel Lesions in Patients with Crohn's Disease: A Systematic Review and Meta-Analysis.

We aimed to evaluate and compare the diagnostic performances of ultrasonography (US) and magnetic resonance enterography (MRE) in assessing active bowel lesions in patients with Crohn's disease (CD). MATERIALS AND METHODS: We searched PubMed and EMBASE for studies in which US and MRE were used to assess active bowel lesions in CD patients. Bivariate random effect meta-analytic methods were used to estimate pooled sensitivity, specificity, and hierarchical summary receiver operating characteristic (HSROC) curves. We performed a meta-regression analysis to explore the source of study heterogeneity. RESULTS: Eleven studies involving 752 patients were included. US exhibited a pooled sensitivity of 86% (95% confidence interval (CI) 72-94), pooled specificity of 88% (95% CI 78-94), and HSROC of 0.93 in 10 studies. MRE exhibited a pooled sensitivity of 88% (95% CI 76-95), pooled specificity of 87% (95% CI 73-95), and an HSROC of 0.94 in eight studies. In seven studies comparing the diagnostic performances of US and MRE, the summary sensitivity of US and MRE were 86% (95% CI 65-96, I2 = 92.1) and 86% (95% CI 72-93, I2 = 88.1) (p = 0.841), respectively. The summary specificity of US and MRE were 87% (95% CI 78-93, I2 = 79.8%) and 84% (72-90, I2 = 72.5%) (p = 0.431), respectively, which showed no statistical differences. On meta-regression analysis, studies from Europe (p = 0.002), those that used linear US probes (p = 0.012), those on small bowel lesions (p = 0.01), and those with outcomes as combined features (active inflammation) reported higher US sensitivity than those from other regions, those that used both linear and convex US probes, those on small and large bowels, and those with outcome as one feature (bowel wall thickening or ulcer). Studies with pediatric patients (p = 0.001), those with reference standards including US (p = 0.001), and outcomes as combined features (p = 0.01) reported higher MRE specificity than those with adult populations, reference standards other than the US, and outcomes as one feature. CONCLUSIONS: In spite of considerable heterogeneity in the included studies, both US and MRE can diagnose active bowel lesions with comparable diagnostic accuracy in patients with CD. The study region, type of US probe, lesion location, investigated outcome for US sensitivity and study population, reference standards, and investigated outcomes for MRE specificity were potential sources of heterogeneity.

Metronomic dose-finding approach in oral chemotherapy by experimentally-driven integrative mathematical modeling.

In conventional chemotherapy, maximum tolerated dose approach is considered as a first-line medication for cancer treatment in clinics. In contrast to the conventional chemotherapy which has heavy tumor burdens arising from high dose treatment, metronomic chemotherapy (MCT) engages relatively low dose without drug-free breaks, and is recognized as a promising strategy for a long-term management of the disease. Although doxorubicin (DOX), an anthracycline anti-cancer drug, showed a potential of maintenance effect in vitro, further study on in vivo-relevant concentration to achieve tumor suppression with no toxicity is required to apply the MCT in clinicals. Therefore, the objective of this study was to identify an optimal MCT regimen of DOX by determining concentration-response relationships of tumor suppression (pharmacodynamic; PD) and cardiac toxicity (toxicodynamic; TD). Utilizing an oral DOX formulation complexed with deoxycholic acid (DOX/DOCA complex) which has enhanced bioavailability, physiologically-based pharmacokinetic (PBPK) model was linked to TD and PD models to generate drug profiles from the combined PK, TD, and PD parameters. The integrated model was validated for various scenarios of administration route, formulation, dose, and frequency. The established mathematical model facilitated calculations of adequate in vivo-relevant dosages and intervals, suggesting the optimum oral metronomic regimen of DOX. It is expected to serve as a useful guideline for the design and evaluation of oral DOX formulations in future preclinical/clinical studies.