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The aim of this study was to evaluate the activity and the safety of a combination regimen of capecitabine and doxorubicin as salvage chemotherapy in advanced gastric cancer patients who had undergone one or two prior chemotherapy regimens. Patients received capecitabine, 2,500 mg/m2/day PO for 14 days (D1–14) and doxorubicin, 30 mg/m2 IV on day 1 every 3 weeks until disease progression. The response was evaluated according to RECIST criteria, and the toxicity was evaluated by NCI-CTC (version 2.0). Forty-five patients were enrolled. Twenty-six patients were treated as second-line chemotherapy and the remaining patients as third-line chemotherapy. A total of 152 cycles of chemotherapy (median 2, range 1–12) were administered. Median dose intensities of capecitabine and doxorubicin were 11,326 and 9.6 mg/m2/week, respectively. The overall response rate was 6.7% (95% CI, 4.1–12.5%) and the disease control rate was 46.7% (95% CI, 28.6–87.1%) according to an intent-to-treat analysis. The median progression-free survival was 11.3 weeks (95% CI, 5.6–16.7 weeks). The median overall survival was 29.1 weeks (95% CI, 18.3–39.9 weeks) with one-year survival rate of 24%. Severe (grade III/IV) hematologic and non-hematologic toxicity was uncommon and included nausea/vomiting in five (11.1%), neutropenia in two (4.4%), anemia in one (2.2%), and hand-foot syndrome in one patient (2.2%). The combination of capecitabine and doxorubicin is a feasible salvage regimen in advanced pre-treated gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose: Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin.Methods: Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m(2 )capecitabine twice daily on days 1-14 and a dose of 100 mg/m(2) irinotecan infused over 90 min on days 1 and 8, every 3 weeks.Results: The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5-58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8-8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9-9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0-15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%).Conclusions: The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin. [ABSTRACT FROM AUTHOR]

This study examined the effects of cognitive-behavioral group therapy (CBT) on the self-esteem, depression, and self-efficacy of runaway adolescents residing in a shelter in Seoul, South Korea. The study used a control group pretest-posttest design. The experimental group and the control group consisted of 14 and 13 male subjects, respectively, with subjects having been randomly assigned to these groups. The experimental group participated in a CBT that consisted of eight sessions over an 8-week period; the control group did not participate in the program. To examine the effects of the CBT on dependent variables, the Wilcoxon signed rank test was used. The scores on depression decreased significantly ( z = -2.325, p = .02) and those on self-efficacy increased significantly ( z = -2.098, p = .03) after the intervention in the experimental group. There was no significant change on self-esteem ( z = -1.19, p = .23). In the control group, the scores on depression, self-esteem, and self-efficacy did not change significantly after the intervention period. The CBT developed in this study consisted of structured and specific content that could be usefully applied to runaway adolescents residing in a shelter. Copyright © 2005 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

The dual tumor-suppressive and -promoting functions of TGF-β signaling has made its targeting challenging. We examined the effects of TGF-β depletion by AVID200/BMS-986416 (TGF-β-TRAP), a TGF-β ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGF-β-TRAP potentiates the efficacy of anti-programmed cell death 1 (anti-PD-1) in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T cells to combination TGF-β-TRAP and anti-PD-1 treatment across several tumor models. Single-nuclear RNA sequencing suggested that TGF-β-TRAP modulates cancer-associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGF-β-TRAP may modulate the CCL5/CCR5 axis as well as costimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGF-β-TRAP and anti-PD-1 combination treatment. This study suggested that TGF-β depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into antitumor immune agonists in PDAC, supporting the validation of such effects in human specimens.

Theranostics, by integrating diagnosis and therapy on a single platform, enables real-time monitoring of tumors during treatment. To improve the accuracy of tumor diagnosis, the fluorescence and photoacoustic imaging modalities can complement each other to achieve high resolution and a deep penetration depth. Despite the superior performance, the biodegradability of theranostic agents plays a critical role in enhancing nanoparticle excretion and reducing chronic toxicity, which is essential for clinical applications. Herein, we synthesize biocompatible and biodegradable indocyanine green (ICG)-conjugated germanium nanoparticles (GeNPs) and investigate their biodistributions in nude mice and 4T1 tumor models after intravenous injections using near-infrared (NIR) dual-modality fluorescence and photoacoustic imaging. The ICG-conjugated GeNPs have strong NIR absorption due to the NIR-absorbing ICG and Ge in combination, emit strong NIR fluorescence due to the multilayered ICG coatings, and exhibit very low in vitro and in vivo toxicity. After tail vein injections, the ICG-conjugated GeNPs mainly accumulate in the liver and spleen as well as the tumor with the help of the enhanced permeability and retention effect. The tumor's fluorescence signal is much stronger than that of the control group injected with pure ICG solution, as the GeNPs can function as biodegradable carriers for efficiently delivering the ICG molecules to the tumor. Lastly, the ICG-conjugated GeNPs accumulated in the tumor can also be utilized for photothermal treatment under NIR laser irradiation, after which the tumor volume almost diminishes after 14 days. The experimental findings in this work demonstrate that the ICG-conjugated GeNPs are promising theranostic agents with exceptional biodegradability for in vivo NIR dual-modality imaging and photothermal therapy.

Charge density waves (CDWs) are pervasive orders in solids that usually enhance the effective mass (m*) and reduce the Fermi velocity ( v F ) of carriers. Here, we report on the inverse - a reduced m* and an enhanced v F correlated with the growth of the CDW order in CuTe with gapped, practically linearly dispersing bands - reminiscent of emergent CDW-gapped topological semimetals. Using momentum-dependent electron energy-loss spectroscopy (q-EELS), we simultaneously capture m* and v F of the CDW-related, practically linearly dispersing electrons by plasmon dispersions across the transition (335 K, T CDW ), with m* of 0.28 m 0 (m 0 , the electron rest mass) and v F of ~ 0.005c (c, the speed of light) at 300 K. With the growth of the CDW order-parameter strength toward 100 K, the electrons become lighter and move faster by ~ 20%. Thorough inspection below T CDW unveils the essential role of the increasing opening of the CDW gap. CuTe is a rich platform for the exploration of CDW/correlation physics with q-EELS established as a useful probe for this type of physics., (© 2024. The Author(s).)

Aim: Studies evaluating the cardiovascular safety of pioglitazone show inconsistent results and ischemic heart disease (IHD) risks associated with different anti-diabetic drugs added to metformin uncontrolled type 2 diabetes mellitus (T2DM) are not assessed. This study aimed to evaluate IHD risk associated with pioglitazone and/or insulin added to patients with metformin uncontrolled T2DM., Methods: Data were extracted from the National Health Insurance Research Database of Taiwan. A total of 19,952 patients with T2DM uncontrolled on metformin received pioglitazone and/or insulin added to metformin were included., Results: Compared to those who never received pioglitazone and/or insulin, patients receiving both insulin and pioglitazone had higher cumulative risk of IHD (adjusted HR [aHR] = 1.911, 95 % confidence interval [CI]: 1.506-2.351), pioglitazone alone (aHR = 1.446, 95 % CI: 1.111-1.775), and insulin alone (aHR = 1.351, 95 % CI: 1.1052-1.684) (all, p < 0.05). Patients who received both pioglitazone and insulin had a higher cumulative risk of IHD than those who received insulin or pioglitazone as well as a similar result in the cumulative defined daily dose (cDDD) of the drugs., Conclusion: Administering pioglitazone plus insulin to patients with T2DM uncontrolled on metformin may increase the risk of IHD, suggesting that other second-line anti-diabetes drugs may be a better choice for patients with T2DM uncontrolled on metformin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Residual brain arteriovenous malformations (BAVMs) following stereotactic radiosurgery are not uncommon and the optimal subsequent management remains undetermined.1-3 Endovascular embolization has been reported as an effective treatment for residual BAVMs after radiosurgery,4 5 and has the advantage over repeat radiosurgery in selected cases as angiographic weak points can be secured immediately and the risk of radiation-induced complications is less of a concern.6 7 In this technical video (video 1), we demonstrate the transvenous embolization of a previously-irradiated arteriovenous malformation and a persistent venous pouch using the retrograde pressure cooker technique, with emphasis on the important recommendations for avoiding periprocedural complications.neurintsurg;jnis-2024-022035v1/V1F1V1Video 1Video demonstrating Onyx embolization of the residual brain arteriovenous malformation using the retrograde pressure cooker technique., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The mortality, long-term morbidity, and exacerbated healthcare needs due to firearm injury in the US are significant and growing. However, the relationship between exposure to a nonfatal firearm injury and long-term ED utilization is poorly understood. This study estimates the association between exposure to a nonfatal firearm injury and ED utilization in the subsequent year., Methods: Using all-payer ED data among non-elderly adults in Georgia and New York, all ED visits for nonfatal firearm injuries from 2017-2018 were identified. Sociodemographic, clinical, and contextual characteristics between nonfatal firearm injury ED patients and the broader population of ED users were compared. ED utilization in the year following a nonfatal firearm injury relative to ED use in the year before, and compared to ED use by a propensity score matched control group was examined, using Poisson and negative binomial multivariable regressions. Analyses were performed in 2024., Results: Nonfatal firearm injury ED patients were disproportionately male, younger, non-Hispanic Black, uninsured, and residents of areas with low median income and high firearm ownership. Compared to a matched control group, multivariable analyses indicated that nonfatal firearm injury ED patients had significantly higher risks of having hospital admissions through the ED (aRR: 1.42), all-cause injury-related ED visits (aRR: 1.47), non-firearm injury-related ED visits (aRR: 1.26), and additional nonfatal firearm injury-related ED visits (aRR: 325.45) in the subsequent year (p<0.001 for all). About one in every eight ED users with a firearm-related injury at index also sought ED care for another nonfatal firearm injury within one year., Conclusions: Nonfatal firearm-related injuries contribute to preventable harm, health inequity and increased ED utilization., Competing Interests: Declaration of competing interest No financial disclosures have been reported by the authors of this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Sarcopenia is linked to increased fall and hip fracture risk. However, studies often overlook comprehensively controlling for age, sex, bone mineral density (BMD), and body mass index (BMI). Our study aimed to determine if sarcopenia, determined by evaluating the psoas muscle volume, is an independent risk factor for hip fractures. We employed a methodological approach that includes the exact matching technique., Methods: In this cross-sectional comparative study, we compared the data of patients who sustained hip fractures between 2015 and 2021 with those of a control group from a health screening center in a single center. The study included 545 patients with hip fractures and 1292 without fractures. We collected data on demographics, BMD determined using dual-energy X-ray absorptiometry, and abdominal and pelvic computed tomography (APCT) scans for psoas muscle volume analysis., Results: The analysis after exact matching of 266 pairs revealed that psoas volume/height 2 was the most significant and dominant risk factor among the evaluated indices. Multivariate logistic regression analysis, adjusting for age, sex, BMI, and BMD, identified height or height 2 -adjusted psoas muscle volume as an independent risk factor for hip fractures (p = 0.042 and p = 0.002, respectively). Age, female sex, lower BMI, and lower BMD were associated with an increased risk of hip fractures., Conclusion: Decreased psoas muscle volume adjusted for patient height independently predicts hip fracture risk. Psoas volume assessment via APCT is a practical tool for identifying at-risk individuals, emphasizing the necessity of including sarcopenia in hip fracture risk assessments., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The type VI secretion system (T6SS) is a molecular machine utilised by many Gram-negative bacteria to deliver antibacterial toxins into adjacent cells. Here we present the structure of Tse15, a T6SS Rhs effector from the nosocomial pathogen Acinetobacter baumannii. Tse15 forms a triple layered β-cocoon Rhs domain with an N-terminal α-helical clade domain and an unfolded C-terminal toxin domain inside the Rhs cage. Tse15 is cleaved into three domains, through independent auto-cleavage events involving aspartyl protease activity for toxin self-cleavage and a nucleophilic glutamic acid for N-terminal clade cleavage. Proteomic analyses identified that significantly more peptides from the N-terminal clade and toxin domains were secreted than from the Rhs cage, suggesting toxin delivery often occurs without the cage. We propose the clade domain acts as an internal chaperone to mediate toxin tethering to the T6SS machinery. Conservation of the clade domain in other Gram-negative bacteria suggests this may be a common mechanism for delivery., (© 2024. The Author(s).)

Background: Improved surgical techniques and more intensive systemic therapy have increased the number of patients with oligometastatic colorectal cancer eligible for resection, but a significant percentage of these cases will ultimately recur. Furthermore, distinct recurrence patterns have been associated with different outcomes., Methods: Data for 195 patients who underwent curative-intent colorectal liver metastasis (CRLM) resection between 2016 and 2022 at Johns Hopkins Hospital were retrospectively collected. Cox regression univariate and multivariate analyses identified features associated with survival outcomes. Association between risk factors and site of recurrences was conducted via logistic regression with initial recurrences grouped into intrahepatic-only, extrahepatic-only, and concurrent intra- and extrahepatic recurrence., Results: The 1- and 2-year recurrence-free survival (RFS) rates were 46% and 22%, respectively. The 1- and 2-year overall survival (OS) rates were 95% and 88%, respectively. The median OS was 71.7 months. Multivariate analysis identified age <60 years, N2 nodal status, R1 liver margin, and higher preoperative carcinoembryonic antigen as top prognostic factors for worse RFS. Additionally, patients with left-sided primary tumors had a higher risk of intrahepatic-only recurrence, whereas mutant KRAS was associated with a higher risk of extrahepatic recurrence with or without liver recurrence., Conclusion: These results from a recent cohort of patients treated with current standard-of-care therapies identify features associated with elevated risk and specific patterns of recurrence. These insights into CRLM recurrence patterns support a larger prospective study to identify subgroups of patients who may require additional therapies to prevent recurrence., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Purpose: Current clinical risk stratification methods for localized prostate cancer are suboptimal, leading to over- and undertreatment. Recently, machine learning approaches using digital histopathology have shown superior prognostic ability in phase III trials. This study aims to develop a clinically usable risk grouping system using multimodal artificial intelligence (MMAI) models that outperform current National Comprehensive Cancer Network (NCCN) risk groups., Materials and Methods: The cohort comprised 9,787 patients with localized prostate cancer from eight NRG Oncology randomized phase III trials, treated with radiation therapy, androgen deprivation therapy, and/or chemotherapy. Locked MMAI models, which used digital histopathology images and clinical data, were applied to each patient. Expert consensus on cut points defined low-, intermediate-, and high-risk groups on the basis of 10-year distant metastasis rates of 3% and 10%, respectively. The MMAI's reclassification and prognostic performance were compared with the three-tier NCCN risk groups., Results: The median follow-up for censored patients was 7.9 years. According to NCCN risk categories, 30.4% of patients were low-risk, 25.5% intermediate-risk, and 44.1% high-risk. The MMAI risk classification identified 43.5% of patients as low-risk, 34.6% as intermediate-risk, and 21.8% as high-risk. MMAI reclassified 1,039 (42.0%) patients initially categorized by NCCN. Despite the MMAI low-risk group being larger than the NCCN low-risk group, the 10-year metastasis risks were comparable: 1.7% (95% CI, 0.2 to 3.2) for NCCN and 3.2% (95% CI, 1.7 to 4.7) for MMAI. The overall 10-year metastasis risk for NCCN high-risk patients was 16.6%, with MMAI further stratifying this group into low-, intermediate-, and high-risk, showing metastasis rates of 3.4%, 8.2%, and 26.3%, respectively., Conclusion: The MMAI risk grouping system expands the population of men identified as having low metastatic risk and accurately pinpoints a high-risk subset with elevated metastasis rates. This approach aims to prevent both overtreatment and undertreatment in localized prostate cancer, facilitating shared decision making.

Objectives: Long sleep duration predicts adverse health outcomes in older adults. Impaired cardiac autonomic control (CAC) is a potential pathomechanism that links this relationship; however, the causal relationship between long sleep duration and CAC remains unclear. This study aimed to determine the temporal relationship between long sleep duration and poor CAC., Methods: This is a community-based, fixed-cohort, follow-up study that recruited community-dwelling older adults aged ≥ 65 years. Self-reported sleep duration was categorized as short (≤ 5 h), mid-range (6-7 h), and long (≥ 8 h). Participants with short or long sleep duration were defined as cases. CAC was measured using heart rate variability (HRV), and cases were classified using cutoffs defined by the lowest quintiles of four HRV parameters. Non-case participants for sleep duration or CAC at baseline were followed. Binary and multinomial logistic regression analyses were conducted to examine baseline variables that predicted incident CAC decline and changes in sleep duration, respectively., Results: A total of 772 individuals were recruited, with a mean follow-up period of 5.8 ± 1.7 years. In multivariable analyses, long sleep duration at baseline predicted a higher risk of cardiac vagal control decline in the follow-up visit (odds ratio: 1.86, 95% confidence interval: 1.00-3.44). Conversely, all HRV parameters at baseline failed to predict changes in sleep duration at the follow-up visit., Conclusions: Long sleep duration seems to precede the decline in CAC in community-dwelling older adults., (© 2024 John Wiley & Sons Ltd.)

Background: Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326)., Methods: Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points., Results: Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage., Conclusions: The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC., (© 2024 Merck Sharp & Dohme LLC and The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aβ accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation., Competing Interests: Declaration of Competing Interest Authors have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC)., Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity., Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D., Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Background: Accurate risk stratification is critical to guide management decisions in localized prostate cancer (PCa). Previously, we had developed and validated a multimodal artificial intelligence (MMAI) model generated from digital histopathology and clinical features. Here, we externally validate this model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial., Objective: To externally validate the MMAI model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial., Design, Setting, and Participants: Our validation cohort included 318 localized high-risk PCa patients from NRG/RTOG 9902 with available histopathology (337 [85%] of the 397 patients enrolled into the trial had available slides, of which 19 [5.6%] failed due to poor image quality)., Outcome Measurements and Statistical Analysis: Two previously locked prognostic MMAI models were validated for their intended endpoint: distant metastasis (DM) and PCa-specific mortality (PCSM). Individual clinical factors and the number of National Comprehensive Cancer Network (NCCN) high-risk features served as comparators. Subdistribution hazard ratio (sHR) was reported per standard deviation increase of the score with corresponding 95% confidence interval (CI) using Fine-Gray or Cox proportional hazards models., Results and Limitations: The DM and PCSM MMAI algorithms were significantly and independently associated with the risk of DM (sHR [95% CI] = 2.33 [1.60-3.38], p < 0.001) and PCSM, respectively (sHR [95% CI] = 3.54 [2.38-5.28], p < 0.001) when compared against other prognostic clinical factors and NCCN high-risk features. The lower 75% of patients by DM MMAI had estimated 5- and 10-yr DM rates of 4% and 7%, and the highest quartile had average 5- and 10-yr DM rates of 19% and 32%, respectively (p < 0.001). Similar results were observed for the PCSM MMAI algorithm., Conclusions: We externally validated the prognostic ability of MMAI models previously developed among men with localized high-risk disease. MMAI prognostic models further risk stratify beyond the clinical and pathological variables for DM and PCSM in a population of men already at a high risk for disease progression. This study provides evidence for consistent validation of our deep learning MMAI models to improve prognostication and enable more informed decision-making for patient care., Patient Summary: This paper presents a novel approach using images from pathology slides along with clinical variables to validate artificial intelligence (computer-generated) prognostic models. When implemented, clinicians can offer a more personalized and tailored prognostic discussion for men with localized prostate cancer., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Viral neutralization (NT) assays can be used to determine the immune status of patients or assess the potency of candidate vaccines or therapeutic monoclonal antibodies (mAbs). Focus reduction neutralization test (FRNT) is a conventional neutralization test (cVNT) with superior specificity for measurement of neutralizing antibodies against a specific virus. Unfortunately, the application of FRNT to the chikungunya virus (CHIKV) involves a highly pathogenic bio-agent requiring biosafety level 3 (BSL3) facilities, which inevitably imposes high costs and limits accessibility. In this study, we evaluated a safe surrogate virus neutralization test (sVNT) that uses novel CHIKV replicon particles (VRPs) expressing eGFP and luciferase (Luc) to enable the rapid detection and quantification of neutralizing activity in clinical human serum samples., Methods: This unmatched case-control validation study used serum samples from laboratory-confirmed cases of CHIKV (n = 19), dengue virus (DENV; n = 9), Japanese encephalitis virus (JEV; n = 5), and normal individuals (n = 20). We evaluated the effectiveness of sVNT, based on mosquito cell-derived CHIK VRPs (mos-CHIK VRPs), in detecting (eGFP) and quantifying (Luc) neutralizing activity, considering specificity, sensitivity, and reproducibility. We conducted correlation analysis between the proposed rapid method (20 h) versus FRNT assay (72 h). We also investigated the correlation between sVNT and FRNT in NT titrations in terms of Pearson's correlation coefficient (r) and sigmoidal curve fitting., Results: In NT screening assays, sVNT-eGFP screening achieved sensitivity and specificity of 100%. In quantitative neutralization assays, we observed a Pearson's correlation coefficient of 0.83 for NT50 values between sVNT-Luc and FRNT., Conclusions: Facile VRP-based sVNT within 24 h proved highly reliable in the identification and quantification of neutralizing activity against CHIKV in clinical serum samples., (© 2024. The Author(s).)

This study examines the relationship between perceived social status, COVID-19-related discrimination, and sleep quality among 158 migrant care workers in Taiwan. Data were collected via computer-assisted interviews, assessing perceived social status with the MacArthur scale and sleep quality using the Pittsburgh Sleep Quality Index. The results revealed that higher perceived social status in reference to the destination country (B = 0.31; 95% confidence interval [CI] = [0.08, 0.53]; P = .008) and experience of media stigmatization (B = 0.52; 95% CI = [0.04, 0.99]; P = .03) were associated with higher global Pittsburgh Sleep Quality Index (PSQI) scores, whereas perceived social status in reference to the home country and others forms of pandemic-related discrimination were not associated with PSQI scores. The study concludes that social comparison and stigmatization linked to sleep health of migrant care workers. Understanding these factors can inform the development of targeted interventions to address inequalities faced by migrants., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Prolonging life is a global trend, and more medical expenditure is being spent on chronic diseases owing to population aging. Diseases commonly seen in middle-aged and elderly people, such as heart disease and diabetes, have slowed mortality improvement in recent years. Diabetes is a common chronic disease and comorbidity of many serious health conditions. The total estimated cost of diabetes in the United States was $327 billion in 2017. However, many people are unaware that diabetes is common, and at least 21.4% of adults do not know that they have diabetes. The number of diabetes-related deaths has been increasing, and diabetes was the 5th cause of death in Taiwan in 2019. In this study, we explore the trend and influence of diabetes in Taiwan and apply mortality models, such as the Lee-Carter and Age-Period-Cohort models, using data from Taiwan's National Insurance to model the incidence and mortality rates of diabetes. We found that the Lee-Carter model provides fairly satisfactory estimates and that people with diabetes regularly taking diabetes medication have lower mortality rates. Moreover, we demonstrate how these results can be used to design diabetes related insurance products and prepare the insured to face the impact of incurring diabetes. In addition, we consider different criteria for judging whether people have diabetes (as there is no consensus on these criteria) and investigate the issue of moral hazard in designing diabetes insurance products., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yue et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Ambulatory blood pressure monitoring (ABPM) is considered the gold standard for proper diagnosis of hypertension. Yet, access to ABPM in the U.S. is limited, and the extent of coverage by commercial health plans remains uncertain, potentially limiting access to ABPM among commercially insured patients., Objective: This study aims to assess the net cost impact of using ABPM in comparison to clinical blood pressure monitoring (CBPM) in the U.S. over a 5-year time period., Design Methods: Using a Markov Model, we estimate the 5-year cumulative cost impact of using ABPM to confirm a prior diagnosis of primary hypertension using CBPM to avoid treatment for white-coat hypertension (WCH) in a hypothetical cohort of 1000 patients from a U.S. healthcare system perspective. The probability and cost inputs for the model were derived from available literature. Base-case model parameters were varied to account for different scenarios., Results: Base-case results indicate using ABPM instead of CBPM over 5 years saves a total of $348,028, reflecting an average per-person-per-year (PPPY) cost saving of $70. In sensitivity analyses, almost all cases reveal ABPM as a cost-saving approach compared to CBPM, with cost savings reaching up to $228 PPPY in the highest hypertension treatment cost model. Regression results reveal that ABPM was cost-saving compared to CBPM if ABPM annual payment rates are $100 or less and annual hypertension treatment costs are ⩾$300., Conclusion: The potential cost-savings of using ABPM instead of CBPM found in our simulation model underscores the need for confirmatory research using real-world data to support increased use of ABPM as the standard diagnostic approach for hypertension., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: This study aimed to assess the current neonatal nutritional practices in Taiwan and promote consensus on standardized protocols., Methods: An online questionnaire comprising 95 items on parenteral nutrition (PN) and enteral nutrition (EN) practices was distributed to neonatal care units across Taiwan via email between August and December 2022. The responses were compared with the recommendations from the European Society for Pediatric Gastroenterology Hepatology and Nutrition for preterm infant care., Results: Most of the 35 neonatal units, comprising 17 level III and 18 level II units, that participated in this study adhered to standard PN protocols; however, only 30% of units used protein-containing solutions as the initial fluid. Over half of the neonatal units provided calcium, phosphate, and magnesium at less than the recommended dosage. Trophic feeding commenced within 48 h in 88% of the units, with the mother's milk used as the first choice. All the units preferred commencing advanced feeding at <25 mL/kg/day., Conclusions: Most nutrient protocols for preterm infants in neonatal units in Taiwan meet recent guidelines, but discrepancies such as lower mineral supplements in PN and a slower advancement of enteral feeding increase nutritional risk. These issues warrant further research.

Treating diabetic wounds effectively remains a significant clinical challenge. Emerging studies suggest that microRNAs (miRNAs) play crucial roles in various physiological and pathological processes and hold promise as therapeutic tools. This study investigates the miRNA expression profile in keratinocytes using a cell model of diabetic wounds. Microarray analysis revealed that 43 miRNAs from wounded keratinocytes incubated under diabetic conditions (high glucose/hypoxia) exhibited a two-fold change in expression compared to those incubated under normal conditions (low glucose/normoxia). Quantitative RT-PCR confirmed significant differences in the expression of eight miRNAs, with miR-3138 and miR-3679-5p being further analyzed for their roles in keratinocyte migration. Transfection with a miR-3138 mimic and a miR-3679-5p inhibitor indicated that upregulation of miR-3138 and downregulation of miR-3679-5p enhance keratinocyte migration in both normal and diabetic wounds. Pathway and gene ontology (GO) analyses identified potential pathways and functional annotations associated with miR-3138 and miR-3679-5p in diabetic wound healing. Potential human gene targets of miR-3138 and miR-3679-5p were predicted using a three-way comparison of the TargetScan, miRDB, and DIANA databases. This study elucidates the miRNA expression signature of human keratinocytes in a diabetes-like environment, providing deeper insights into the pathogenesis of diabetic wounds.

This study investigates the extent to which different genotypes can explain changes in body mass following an 8-week running program, in a UK population. Participants were randomly assigned to either a training ( n  = 17) or control group ( n  = 21). Participants' diets were not altered, only the exercise regime was manipulated to isolate effects. The exercise group completed a periodized running program consisting of 20-30 min, over an agreed route, three times per-week, whilst the control groups refrained from daily exercise. Participants were screened at the end of the study for 1,000 gene variants using a DNA test kit. Results demonstrated a significant reduction in body mass, within the exercise, compared to the control group ( p  = .002). This reduction in body mass varied significantly ( p  = .024) between individuals within the exercise group. Moreover, genetic analysis identified 17 single nucleotide polymorphisms (SNPs) associated with this variation (r 2  = .74; p  < .001). These findings indicate that individuals with specific alleles are better predisposed to weight-management, compared to their counterparts, following an exercise program. This study helps to bridge the gap between population health and exercise science and can inform research in the application of genetics to help develop individually tailored health interventions.

Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a type I arginine methyltransferase-DEAD-box polypeptide 3, X-linked (PRMT1-DDX3) axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates phosphatase and tensin homology-induced kinase 1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer. Significance: DDX3 is stabilized by PRMT1-mediated arginine methylation and coordinates mitophagy and mitochondrial biogenesis by upregulating PINK1 to facilitate breast cancer progression., (©2024 American Association for Cancer Research.)

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases., (© 2024. The Author(s).)

Background: High-grade gliomas (HGG) are the most aggressive primary brain tumors with poor prognoses despite conventional treatments. Immunotherapy has emerged as a promising avenue due to its potential to elicit a targeted immune response against tumor cells., Objective: This meta-analysis aimed to evaluate the efficacy and safety of various immunotherapeutic strategies, including immune checkpoint inhibitors (ICI), virotherapy, and dendritic cell vaccines (DCV) in treating HGG., Methods: Following the PRISMA framework, we searched PubMed, Cochrane, and Embase for studies reporting outcomes of HGG patients treated with immunotherapy. Key metrics included overall survival, progression-free survival, and treatment-related adverse events., Results: We reviewed 47 studies, analyzing data from 3674 HGG patients treated with immunotherapy. The mean overall survival for patients treated with ICI was 11.05 months, with virotherapy at 11.79 months and notably longer for DCV at 24.11 months. The mean progression-free survival (PFS) for ICIs was 3.65 months. Virotherapy demonstrated a PFS favoring the control group, indicating minimal impact, while DCV showed substantial PFS improvement with a median of 0.43 times lower hazard compared to controls (95% CI: 29-64%). Adverse events were primarily Grade 1 or 2 for ICI, included a Grade 5 event for virotherapy, and were predominantly Grade 1 or 2 for DCV, indicating a favorable safety profile., Conclusion: Immunotherapy holds potential as an effective treatment for HGG, especially DCV. However, results vary significantly with the type of therapy and individual patient profiles. Further randomized controlled trials are necessary to establish robust clinical guidelines and optimize treatment protocols., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Gamma knife radiosurgery (GKRS) for orbital cavernous hemangioma (OCH) has emerged as a promising method due to its significant clinical improvement and low incidence of complications. This study aimed to evaluate the safety and efficacy of GKRS for the treatment of OCH., Methods: In accordance with the PRISMA framework, we searched PubMed, Cochrane Central, and Embase for studies reporting outcomes of GKRS for OCH. Studies reporting complications, visual improvement, proptosis, tumor reduction rate, and tumor progression rate for OCH following GKRS were included., Results: Six studies, out of 1856 search results, with 100 patients were included. Among them, only 5 minor complications were related to GKRS, including 3 with orbital pain and 2 with periorbital chemosis. Thus, the complication rate was 13% (95% CI, 7-25%). Visual acuity and visual field improvement rates after GKRS were 80% (95% CI, 63-96%) and 71% (95% CI, 47-95%) respectively. Proptosis improved in 94% of cases (95% CI, 83-100%). The tumor reduction rate was 77% after GKRS (95% CI, 69-85%)., Conclusion: GKRS for OCH appears to be a safe technique, as evidenced by the rate of clinical improvement and radiological improvement. However, studies are limited by an absence of a control group. Additional studies are needed to evaluate the relative efficacy of GKRS as compared with alternative surgical modalities for OCH., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)