Background: Smoking prevalence among people in substance use treatment is substantially higher than the national average. Residential substance use treatment represents an opportune time to address this disparity. California launched the Tobacco Free for Recovery Initiative to help residential substance use treatment programs implement tobacco-free grounds policies and increase smoking and other tobacco cessation services. Eleven programs that participated in the initiative were revisited over two years later to examine the sustainability of changes made during the initiative. Methods: Directors in each of the treatment programs participated in semi-structured interviews. Thematic analysis methods and an implementation science framework were applied to investigate research questions. Results: Over half of the programs (n = 6; 54.5%) remained tobacco free after two years. The other five programs (45.5%) reverted their policies or had never implemented tobacco free grounds. All programs reported offering smoking cessation services at the time of interview, irrespective of tobacco free policies. Directors identified barriers and supports for sustainability and described ongoing needs. Conclusions: Guided by an implementation framework, results from this study offer recommendations for how to support residential substance use treatment programs in addressing smoking prevalence among clients.
Embryonic stem (ES) cell-based platforms in non-model teleosts remain scarce, which may constrain in vitro studies in functional genomics and developmental biology in aquaculture-relevant species. Here, we report the derivation and characterisation of ATES1, an ES-like cell line derived from Anabas testudineus, a commercially important freshwater fish. ATES1 has been maintained for over 250 passages (> 1500 days) under feeder-free conditions in Leibovitz-15 medium supplemented with foetal bovine serum, fish serum, embryo extract, and human basic fibroblast growth factor (hbFGF). Proliferation was optimal at 28 °C, with both fish serum and hbFGF significantly enhancing cell growth. The cell line exhibited multiple characteristics associated with ES-like cells in vitro during early passages (approximately up to passages 25-35), including ES cell-like morphology, high self-renewal capacity (5-bromo-2'-deoxyuridine incorporation > 90% and a doubling time of 39.9 h), alkaline phosphatase activity, responsiveness to differentiation induction conditions, and expression of stemness-associated genes (sox2, klf4, sall4, nanog, myc). Immunocytochemistry confirmed Sox2 protein expression. However, real-time PCR revealed a significant decline in klf4 and sall4 expression, along with a lack of responsiveness to differentiation cues, increased heterogeneity, and the emergence of chromosomal abnormalities, suggesting compromised maintenance of ES-like properties during extended passaging. Despite these limitations, ATES1 remained continuously proliferative under feeder-free conditions and supported moderate to high (~ 45.8 ± 4.26%) non-viral transgene delivery efficiency via lipofection, suggesting its potential utility as a genetically manipulable in vitro system for future cellular and biotechnological applications in Anabas testudineus.
Locally advanced nasopharyngeal carcinoma (LA-NPC) shows substantial variability in progression-free survival (PFS) despite radiotherapy-based treatment. Clinical factors and conventional radiomics may not adequately characterize the spatial organization of intratumoral heterogeneity. Whether topology-aware MRI measures are associated with PFS and transcriptomic features remains unclear. To evaluate an MRI-derived intratumoral heterogeneity (ITH) framework for PFS risk stratification and explore its transcriptomic correlates in LA-NPC. Retrospective prognostic modeling study with internal and independent external validation and a separate prospective RNA-sequencing cohort. The retrospective cohort included 1001 patients (747 men and 254 women): training, n = 562; internal validation, n = 241; and external validation, n = 198. The prospective RNA-sequencing cohort included 53 patients (38 men and 15 women). Pretreatment 3.0-T axial contrast-enhanced T1-weighted fast/turbo spin-echo MRI. Primary tumors were manually segmented and reviewed by two senior radiologists. 2D and 3D ITH scores and conventional radiomics features were evaluated using survival models. Transcriptomic correlates were assessed using differential expression, co-expression network, and gene set enrichment analyses. Model discrimination was assessed using the concordance index (C-index) with 95% confidence intervals. Shapley additive explanations (SHAP) were used for model interpretation. Transcriptomic analyses used Benjamini-Hochberg false discovery rate (FDR) correction. The integrated heterogeneity-clinical DeepSurv model yielded C-indices of 0.727 (95% CI, 0.674-0.782) in the internal validation cohort and 0.714 (95% CI, 0.661-0.770) in the external validation cohort. The 3D ITH score had the largest mean absolute SHAP value (0.0554) among the model predictors. High 3D ITH scores were associated with enrichment of cytokine-cytokine receptor interaction (normalized enrichment score [NES] = 1.57; FDR = 0.00705) and viral protein interaction with cytokine and cytokine receptor signaling (NES = 1.77; FDR = 0.00264). MRI-derived 3D ITH contributed to retrospective PFS risk stratification and showed exploratory cytokine-related transcriptomic correlates that require independent validation. 3. Stage 2. Given that intratumoral heterogeneity (ITH) is closely associated with variable outcomes in locally advanced nasopharyngeal carcinoma, its noninvasive assessment may hold prognostic importance. Accordingly, using pretreatment contrast‐enhanced MRI, this study investigated a 3D ITH scoring framework across 1001 retrospective patients and a 53‐patient prospective transcriptomic cohort. Compared with clinical‐only models, the integrated heterogeneity‐clinical model exhibited more reliable progression‐free survival prediction in both internal and external validation sets. Importantly, higher ITH scores were associated with enriched cytokine‐related immune pathways, suggesting that MRI‐derived ITH score may provide an additional prognostic and biological perspective on this malignancy.
Suzetrigine, a non-opioid voltage-gated sodium channel 1.8 (NaV1.8) pain signal inhibitor with no addiction potential, is approved in the USA for moderate-to-severe acute pain. In this phase 4, single-arm study, suzetrigine (100 mg preoperatively, then 50 mg every 12 h) was administered as part of multimodal therapy (MMT) for ≤ 14 days. Participants (N = 47) underwent arthroscopic or laparoscopic procedures wherein opioids are commonly used ≥ 72 h postoperatively for pain management. Pre- and postoperative MMT was prespecified as suzetrigine, acetaminophen, and ibuprofen. Oxycodone or hydromorphone were permitted as opioid rescue. The primary endpoint was the proportion of participants reporting good/very good/excellent on a patient global assessment (PGA) for pain control after treatment. Opioid rescue and safety were also assessed. Participants had various surgeries, the most common being arthroscopic knee procedures (38.3%) or rotator cuff repair (17.0%), and laparoscopic hernia repair with mesh (29.8%). Most participants (90.9%) rated suzetrigine as part of MMT as good/very good/excellent on a PGA for pain control at end of treatment; results were consistent across surgeries. A majority of participants (76.1%) did not require opioid rescue; those who did received 2.2 tablets (mean) after surgery (mean: 1.7 days). Suzetrigine was generally safe and well tolerated. One participant had a serious adverse event (aspiration) considered unrelated to suzetrigine. Adverse events were consistent with postoperative settings. Suzetrigine demonstrated effective pain management and enabled opioid-free recovery for most participants when initiated preoperatively and as part of MMT in arthroscopic or laparoscopic procedures wherein opioids are commonly used postoperatively for pain management. In studies of similar surgeries, < 50% did not require opioids. Graphical abstract available for this article. NCT06887959.
Frailty, defined by multisystem physiological decline and heightened vulnerability to stressors, is typically associated with aging and chronic disease. However, its relevance in apparently healthy individuals remains poorly understood. Identifying frailty in this population could inform primary prevention, as these individuals often remain outside healthcare systems. We investigated the association between frailty and incident chronic conditions and mortality in middle-aged adults free of chronic disease at baseline. Using UK Biobank data, we included 183,783 participants (53.6% female; median age 54 years) without chronic conditions. Frailty was assessed via the Fried frailty phenotype. Cox regression and multi-state models, adjusted for sociodemographic and lifestyle factors, analyzed associations with all-cause and cause-specific mortality, and with overall and organ system-specific incident chronic conditions. At baseline, 1.4% of participants were frail and 34.7% prefrail. Over a median follow-up of 13.8 years, mortality was 9.1% in frail versus 4.1% in robust (non-frail, fit) individuals, and 60.5% versus 48.2% developed at least one chronic condition. Frailty was associated with higher hazards of all-cause mortality (HR 1.92, 95% CI 1.68-2.20) and incident chronic conditions (HR 1.34, 95% CI 1.27-1.41), as well as increased risk of death following disease onset. Associations persisted after excluding events within 10 years of follow-up and were observed across multiple disease categories, including circulatory diseases, independent of key biological risk markers. Similar patterns were noted for prefrailty. Frailty identifies a subgroup of apparently healthy middle-aged adults at increased long-term risk of mortality and chronic disease, suggesting its potential as an early, actionable marker for prevention strategies.
Medullary thyroid cancer (MTC) is an aggressive tumor for which surgery is the only curative treatment. However, after surgery, some patients may experience persistence/recurrence. It is important to identify the prognostic factors that may affect structural disease-free survival (SDFS), which may influence the follow-up of our patients. To assess SDFS in patients with MTC and related factors. A retrospective observational study was conducted in a tertiary hospital including patients with MTC without distant metastases. The following variables were assessed: sex, age, heritability, type of surgery, calcitonin (Ct) and CEA, tumor size, stage, lymph nodes ratio (LNR), vascular invasion, high risk, structural disease, and SDFS. A descriptive and comparative univariate and multivariate analysis of SDFS was performed using SPSS version.29 and Cox regression, defining structural disease as the event. p < 0.05 was considered statistically significant. A total of 140 patients with a median age of 34 years were evaluated. Forty-six percent (n = 65) were male. Twenty-two percent (n = 31) had sporadic MTC, 75% (n = 106) had MEN2a, and 2% (n = 3) had MEN2b. The median calcitonin level was 182.5pg/mL and median follow-up was 179.5 months. Structural disease occurred in 24% of patients (n = 33). The variables that influenced the SDFS were as follows: sporadic CMT, older age, preoperative CEA, size, lymph node involvement, higher LNR, vascular invasion and high risk, and Ct levels > 150pg/mL at 6-12 months. In the multivariate analysis, age, LNR, T category, and postoperative Ct remained independent predictors. The SDFS in MTC is significantly influenced by LNR, T category, and postoperative Ct levels at 6-12 months.
Lead-free halide double perovskites have emerged as promising alternatives to toxic lead-based perovskites for optoelectronic and photovoltaic applications due to their structural stability and tunable physical properties. In this work, the structural, mechanical, electronic, optical, and bonding properties of A2AgSbBr6 (A = Na, K, and Rb) double perovskites were systematically investigated using first-principles calculations. The cubic phase stability of all compounds was confirmed through tolerance and octahedral factors together with elastic stability criteria. Electronic calculations revealed indirect semiconducting band gaps that vary with the A-site ionic radius. Mulliken and Hirshfeld population analyses indicated mixed ionic-covalent bonding characteristics, with Sb-Br bonds exhibiting the strongest covalent nature. Mechanical analysis showed ductile behavior for all compounds, while Na- and K-based systems exhibited relatively higher stiffness. Optical investigations demonstrated strong light absorption and significant optical response in the visible near-UV regions, suggesting potential applications in photovoltaic and optoelectronic devices. Among the investigated compounds, K2AgSbBr6 exhibited the most favorable combination of electronic and optical properties. First-principles calculations were performed within the framework of Density Functional Theory (DFT) using the CASTEP code based on the plane-wave pseudopotential method. The exchange-correlation effects were treated using the generalized gradient approximation (GGA) with the Perdew-Burke-Ernzerhof (PBE) functional. Structural optimization was carried out using the Broyden-Fletcher-Goldfarb-Shanno (BFGS) minimization scheme with ultrasoft pseudopotentials and Monkhorst-Pack k-point sampling. The electronic, mechanical, optical, and bonding properties were calculated using the optimized crystal structures.
Histone post-translational modifications (PTMs) are key regulators of chromatin architecture and gene expression. Although mass spectrometry (MS)-based data-independent acquisition (DIA) pipelines for histone PTM quantification are available, multiplexed targeted assays remain underdeveloped. Here, we present a derivatization-free parallel reaction monitoring (PRM) workflow for robust, quantitative, and site-specific analysis of major histone H3 and H4 PTMs. We employed highly efficient ArgC digestion to generate peptides of optimal length for liquid chromatography-tandem mass spectrometry (LC-MS/MS) while preserving endogenous PTMs, and we optimized chromatographic conditions to achieve isobaric separation and stable retention times. Co-eluting isobaric PTM species were confidently distinguished using site-specific fragment ions. The resulting PRM method enabled sensitive and reproducible detection of histone PTM isoforms across diverse biological systems. To illustrate its utility, we analyzed PTM dynamics in cells expressing histone H3.3 lysine-to-methionine substitutions and in cells treated with the histone deacetylase inhibitor entinostat, yielding results that correlated strongly with antibody-based readouts. This PRM platform provides a complementary, targeted approach to current chemical derivatization-based methods, enabling reliable validation of selected histone PTMs.
The objective was to investigate the impact of graded levels of non-essential amino acids (NEAA) in soybean meal (SBM)-free diets on intestinal health and growth of nursery pigs. Thirty-two pigs weaned on d 21 of age with body weight (BW) of 6.7 ± 0.1 kg, were assigned to one of four diets in a randomized complete block design with BW and sex as blocks. Pigs were fed for 28 d in 3 phases (10, 12, and 6 d, respectively). The diets consisted of a typical corn-SBM diet with supplemental lysine, methionine, and threonine, containing SBM at 19%, 22%, and 27% in phases 1, 2, and 3, respectively (NC), and SBM-free diets supplemented with 0% (PC), 50%, and 100% of NEAA provided by SBM in the NC. All diets met the requirements of essential amino acids. Pigs were housed individually and euthanized on d 28 to collect the jejunal tissue and mucosa to determine the jejunal mucosa-associated microbiota and immunity. The PROC MIXED of SAS was used with treatment as a fixed effect and initial BW and sex as random effects. Contrasts were used to compare the NC and PC and determine linear effects of NEAA levels. The PC reduced (P < 0.05) the expression of toll-like receptor 2 and 4 in the jejunum compared with the NC. Increasing NEAA tended to linearly increase (P = 0.075) the expression of toll-like receptor 4 and linearly increased (P < 0.05) the expression of cluster of differentiation 14 in the jejunum. The PC increased (P < 0.05) interleukin-8 but reduced (P < 0.05) immunoglobulin A in the jejunal mucosa compared with the NC. Increasing NEAA linearly reduced (P < 0.05) interleukin-8 but increased (P < 0.05) immunoglobulin A. The PC reduced (P < 0.05) fecal nitrogen excretion from d 22 to 28 compared with the NC. The PC reduced (P < 0.05) weight gain and gain:feed from d 0 to 28 compared with the NC. Increasing NEAA linearly increased (P < 0.05) weight gain from d 22 to 28 and gain:feed from d 0 to 28. In conclusion, feeding the SBM-free diet meeting requirements of essential amino acids reduced fecal nitrogen excretion, but impaired jejunal immune responses and growth compared with pigs fed the NC. Increasing NEAA improved jejunal immune responses and growth, and at least 100% of the NEAA levels provided by SBM in the typical corn-SBM diet with supplemental lysine, methionine, and threonine may be necessary to optimize growth in nursery pigs fed SBM-free diets. Non-essential amino acids (NEAA) are mostly sufficient in typical pig diets and can also be provided by the conversion from other amino acids and nitrogen sources, and therefore, supplementation of NEAA is not likely needed unless the diet has limited amino acids and nitrogen sources. However, NEAA may need to be considered when formulating low-protein diets due to limited supply of NEAA. The objective of this study was to investigate the impact of graded levels of NEAA in soybean meal (SBM)-free diets on intestinal health and growth of nursery pigs. Feeding the SBM-free diet meeting requirements of essential amino acids reduced fecal nitrogen excretion, but impaired jejunal immune responses and growth compared with pigs fed the typical corn-SBM diet with supplemental lysine, methionine, and threonine. Increasing NEAA improved jejunal immune responses and growth in nursery pigs fed SBM-free diets.
Premenstrual syndrome (PMS) and dysmenorrhea (menstrual pain) are common among women of reproductive age. Fluctuations in reproductive hormone levels during the late luteal phase have been linked to changes in eating and sleep patterns, which may contribute to PMS and dysmenorrhea. This study examined the associations of meal timing and sleep timing with PMS symptoms and dysmenorrhea. In this cross-sectional study, 426 Japanese women (mean age: 33 ± 5 years; body mass index: 22.2 ± 4.3 kg/m2) were recruited via the Asken mobile health application. Participants completed questionnaires assessing PMS symptoms, dysmenorrhea, meal timing (time of first meal, time of last meal, and eating window), sleep timing (wake-up time, bedtime, and sleep duration), chronotype (individual preference for earlier or later sleep-wake timing), and social jetlag (differences between sleep timing on workdays and free days). Multivariable regression models were used after adjusting for age, BMI, smoking status, and alcohol consumption. On workdays, later first meal (β = 0.211) and earlier wake-up time (β = -0.184) were associated with higher eating-related PMS symptoms. On free days, earlier first meal (β = -0.191), later last meal (β = 0.162), longer eating window (β = 0.133), later wake-up time (β = 0.308), and longer sleep duration (β = 0.147) were associated with higher dysmenorrhea severity. Lower breakfast frequency (β = -0.13) was associated with higher eating-related PMS symptoms. Higher afternoon snacking was associated with higher total PMS symptoms (β = 0.13), higher eating-related PMS symptoms (β = 0.11), and higher sleep-related PMS symptoms (β = 0.11). More frequent nighttime snacking was associated with higher odds of moderate-to-severe PMS symptoms (OR = 1.11, 95% CI = 1.00-1.23). Meal and sleep timings were differentially associated with PMS symptoms and dysmenorrhea across workdays and free days. Workday behaviors were primarily associated with eating-related PMS symptoms, whereas free-day behaviors were primarily associated with dysmenorrhea severity. These findings suggest that menstrual symptoms may be differentially associated with behaviors shaped by socially imposed schedules and circadian preferences. Future longitudinal and interventional studies are needed to clarify causal relationships between meal timing, sleep timing, and menstrual health.
Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) arising from the nonfacing sinus presents a significant technical challenge because direct reimplantation may not be feasible due to insufficient coronary length. We describe a dual aortic-pulmonary flap technique enabling anterior tension-free reimplantation.A 6-month-old infant with mildly reduced left ventricular systolic function secondary to ALCAPA originating from the anterior nonfacing pulmonary sinus underwent surgical repair. Following maximal coronary mobilization, a large anterior pulmonary artery flap and a posterior-based aortic flap were constructed and sutured together to create a tubular native arterial extension, permitting tension-free anterior implantation. The anterior pulmonary valve commissure was temporarily detached and subsequently resuspended.Following reimplantation, left ventricular ejection fraction improved from 54% preoperatively to 62% at discharge and mitral regurgitation regressed from moderate to trivial at 1-year follow up. Good coronary artery flow was demonstrated on echocardiogram and the patient remains asymptomatic at 1-year follow up.The dual-flap technique provides additional coronary length using exclusively native arterial tissue and facilitates anterior tension-free reimplantation in selected cases of nonfacing sinus ALCAPA. Further follow up is required to determine long-term durability.
The threshold interpretation of R0 can fail to describe elimination in epidemic models with imperfect vaccination and reinfection. We study an SEIRV model in which vaccinated individuals remain partially susceptible and recovered individuals may be reinfected. The main novelty is an explicit threshold account of how reinfection can sustain endemic equilibria even when the vaccinated-population reproduction number satisfies R0<1. We derive the disease-free equilibrium, R0, and a sufficient condition for convergence to the disease-free state, showing why local disease-free stability and global elimination are distinct. We reduce the endemic-equilibrium problem to a scalar equation and identify a reinfection threshold β2∗ determining the local direction of bifurcation at R0=1. When β2>β2∗, we prove a lower critical threshold R0C<1 separating elimination from subcritical endemic persistence. We also give an efficient-vaccine approximation and general numerical algorithm for computing R0C. Simulations using an illustrative Omicron-era parameterisation show how these thresholds organise the model dynamics.
Elderly PCa patients often present with comorbidities, increasing the risk of complications of pelvic RT and long-term ADT. The aim of the present study is to evaluate the efficacy and safety of personalized UHRT+/- ADT in this setting. Men aged ≥75 years with localized PCa who underwent curative UHRT to the prostate (5 fractions every other day, 6.5-7.25 Gy/fraction) were retrospectively included. Adverse events (AEs) were assessed according to RTOG scale. Biochemical recurrence (BR) and clinical progression (CP) progression-free survival (PFS) were analyzed using Kaplan-Meier estimator. A total of 226 patients was included. Median age at diagnosis was 79 years; Median CCI was 4. The majority (53%) were diagnosed with high or very high risk PCa. Concomitant ADT was administered to 165 (73%) with a median duration of 12 months.At a median follow-up of 2.3 years (available for 217/226), 44 (20%) experienced BR and among these, 31/44 (70%) developed CP. Patients who developed CP were predominantly in high- and unfavorable intermediate-risk groups. Most CPs (61%) were oligoprogressive, and 9 occurred within the treatment field. The 1-, 2-, and 3-year BR-free survival (BRFS) of 98%, 88%, and 82%, respectively. No clinical or treatment-related factor was significantly associated with BRFS or CPFS in the univariate analysis.Acute AEs were limited, with no acute GI in 91% and no acute GU in 56% of patients. Late AEs were also favorable, with 75% and 88% reporting no late GU and GI AEs, respectively. Acute GU AEs correlated with older age and higher comorbidity burden, while acute GI AEs were associated with larger prostate CTV volumes. These findings suggest that personalized UHRT ± ADT provides an acceptable disease control with a safe AE profile in elderly PCa patients, representing a feasible alternative to conventional treatment approaches.
The exploration-exploitation trade-off is ubiquitous in our everyday lives, and individuals display considerable variability in their preferred decision-making strategies. Most previous work pertaining to neural signatures of exploration is restricted to functional pathways. However, the specific contributions of cortical microarchitectures to high-level cognitive processes such as decision-making are as yet unknown. Here, we investigated the neuroanatomical foundations of inter-individual variability in decision-making strategies. To this end, 122 healthy participants completed a gamified multi-armed bandit paradigm aimed at teasing apart distinct exploration-exploitation decision strategies. We also collected whole-brain quantitative MRI maps indexing microstructural features of cortical myelination and iron content. Through computational modelling, we disentangled individual-specific exploration strategies, including value-free random exploration. Whole-brain regression analyses identified significant associations between value-free exploration and increased cortical myelination in right frontal brain areas with reported links to impulsivity. By elucidating the brain microstructural correlates of distinct exploration-exploitation strategies, we aimed to further our understanding of why individuals differ in their decision-making capabilities, and how decision-making may become aberrant in mental health conditions.
VEGFR-2 is a key regulator of tumor angiogenesis and a validated target in anticancer drug discovery. In this study, a series of novel benzanilide derivatives (7a-7f and 9a-9b) were designed, synthesized, and evaluated as potential VEGFR-2 inhibitors. The design strategy was guided by key pharmacophoric requirements for VEGFR-2 inhibition. All compounds were synthesized successfully and characterized, then screened for in vitro cytotoxic activity against MCF-7, MDA-MB-231, HePG-2, and HCT-116 cancer cell lines, with WI-38 and WISH normal cells used for selectivity assessment. Among the tested compounds, 7e emerged as the most potent derivative, exhibiting IC50 values ranging from 8.49 to 11.21 µM across cancer cell lines, comparable to sorafenib. Importantly, 7e also demonstrated favorable selectivity toward cancer cells with a promising selectivity index profile. Mechanistic studies revealed that compound 7e significantly inhibited VEGFR-2 kinase activity (IC50 = 1.79 ± 0.05 µM), supporting its targeted anti-angiogenic mechanism. Flow cytometry analysis showed that 7e induced G0/G1 cell cycle arrest and markedly increased apoptotic cell populations. This was further confirmed by upregulation of Bax, Caspase-3, and Caspase-8, alongside downregulation of Bcl-2, indicating activation of both intrinsic and extrinsic apoptotic pathways. Interestingly, 7e inhibited cancer cell migration, suggesting a potential anti-angiogenetic effect. Density functional theory (DFT) calculations revealed that 7e possesses a conjugated electronic system with a suitable frontier orbital distribution, moderate HOMO-LUMO gap, and a favorable electrostatic potential for receptor interaction. Molecular docking and dynamics simulations demonstrated stable binding of 7e within the VEGFR-2 active site, supported by consistent RMSD, hydrogen bonding, and compact structural behavior. MM-GBSA calculations confirmed favorable binding free energy, while per-residue decomposition and protein-ligand interaction fingerprint analysis identified key stabilizing interactions. Essential dynamics and free energy landscape mapping further confirmed a stable and energetically favorable conformational state. ADMET and toxicity predictions indicated acceptable pharmacokinetic properties, low mutagenic risk, and an overall favorable safety profile. Collectively, these findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
Biliary tract cancer (BTC) remains a formidable clinical challenge owing to its asymptomatic early stages, anatomical complexity, and lack of reliable and noninvasive diagnostic tools. Although traditional tissue biopsy is often limited by invasiveness and sampling bias, liquid biopsy, particularly the analysis of tumor-derived exosomes, has emerged as a promising and clinically relevant alternative for early detection and longitudinal monitoring. Exosomes are specialized extracellular vesicles that sequester diverse molecular cargo including proteins, lipids, and nucleic acids, thereby reflecting the physiological state of their parental tumor cells. However, the clinical translation of exosomal biomarkers is often hindered by technical challenges in achieving high-purity isolation and ultrasensitive detection in complex biological matrices, such as blood and bile. To address these limitations, this review provides a comprehensive overview of recent advancements in nanotechnology-enabled platforms designed to overcome these challenges. First, we examined sophisticated nanostructured systems, such as immuno-magnetic nanoparticles and microfluidic nanoVelcro chips, for high-yield exosome enrichment. Subsequently, we investigated next-generation biosensing modalities with a focus on surface-enhanced Raman scattering for label-free molecular fingerprinting and CRISPR-Cas-integrated nanosensors for amplification-free nucleic acid detection. Significant emphasis has now been placed on the integration of artificial intelligence and deep learning algorithms, which have become indispensable for deciphering complex exosomal signatures to differentiate BTC from benign conditions such as cholangitis. Finally, we discuss the emerging clinical significance of bile-derived exosomes and remaining challenges in standardizing nanomedicine-based liquid biopsies for precision oncology. These integrated platforms could potentially redefine the BTC management paradigm by bridging the gap between advanced nanomaterials and clinical diagnostics.
Immune checkpoint inhibitors (ICIs), alone or combined with chemotherapy, constitute the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) without actionable oncogenic drivers. However, radiologic response assessment has limitations in capturing early biological treatment effects. Tumor-informed circulating tumor DNA (ctDNA) monitoring has emerged as a promising biomarker for early evaluation of treatment efficacy during immunotherapy. We conducted a prospective, single-center, longitudinal observational study including patients with stage IV NSCLC treated with first-line pembrolizumab with or without platinum-based chemotherapy between December 2021 and December 2024. Personalized, tumor-informed ctDNA assays (Signatera™, Natera, Inc.) were designed from tumor tissue and matched normal blood samples and applied to serial plasma samples collected at baseline (prior to ICI initiation) and every six weeks on-treatment. Early ctDNA dynamics were assessed from baseline to the first on-treatment assessment (six weeks post-treatment initiation) and were correlated with radiologic response assessed by RECIST v1.1, objective response rate (ORR), and progression-free survival (PFS). Fifteen patients were enrolled; baseline ctDNA positivity was observed in 13 (87%) patients. Among patients with ctDNA positivity, 11 (85%) experienced a molecular response characterized by ctDNA decrease (n = 1) or clearance (n = 10), while 2 (15%) showed an increase. Early molecular response was strongly associated with radiologic response, with a significantly higher ORR among patients with ctDNA clearance or decrease compared with those with ctDNA increase (91% vs 0%, p = 0.038). Early ctDNA change correlated with percentage change in target lesion size (Spearman R = 0.81, p < 0.001). Longitudinal monitoring demonstrated sustained ctDNA clearance or decrease in patients with durable disease control, while ctDNA positivity preceded radiologic progression. Patient-level survival analysis showed longer progression-free survival intervals predominantly among patients with early ctDNA clearance or decrease. Early clearance or decrease in ctDNA levels strongly predicted radiographic response in advanced NSCLC treated with first-line pembrolizumab with or without chemotherapy. ctDNA dynamics may complement radiological assessment and support more personalized, timely, and biologically informed treatment decisions in advanced NSCLC.
GaAs heteroepitaxy on Ge(100) is an established route for III-V-on-IV integration, yet growth on non-(100) orientations, such as (111), remains underexplored. Here, we systematically investigate the growth of GaAs/Ge(100)-6° and GaAs/Ge(111) by metalorganic chemical vapor deposition (MOCVD) using triethylgallium (TEGa) and arsine (AsH3) precursors at various substrate temperatures and precursor flows. Atomically smooth GaAs surfaces on Ge(111) with root mean squared (RMS) roughness as low as 0.35 nm were realized at 650 °C. Varying the AsH3 flow reveals a coupling between smoothness and twin density, with a 240 sccm AsH3 flow yielding virtually twin-free films with <1 nm RMS roughness. In contrast, the (100)-6° orientation showed a stronger morphological sensitivity with AsH3 flow, exhibiting roughening below 120 sccm. X-ray diffractionboth high-resolution (HR-XRD) and three-dimensional (3D-XRD)and electron microscopyscanning (SEM) and high-angle annular dark field scanning transmission (HAADF-STEM)reveal low twin density films below 0.01% on the optimized Ge(111) and defect-free layers with minimal roughening at the GaAs/Ge interface. Atomic resolution energy-dispersive X-ray spectroscopy (EDS) reveals that the GaAs polarity is (111)-B. These results define the first MOCVD growth parameter map for GaAs/Ge(111), demonstrating scalable, low-defect, polarity-controlled epitaxy suitable for integrating GaAs-based devices on group-IV platforms.
Yogurt is one of the most technologically mature fermented dairy products on the market, traditionally prepared using the two lactic acid bacteria (LAB) Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus. Global demand for yogurt continues to rise, driven by consumer interest in healthy, high-protein diets with as few additives as possible. New lactose-free variants and sugar-reduced yogurts appeal to large consumer segments that either have poor lactose tolerance or focus on a healthy lifestyle. Despite developments in yogurt manufacturing technologies and yogurt starter cultures, some persistent challenges associated with yogurt remain, for example, post-acidification problems, texture instability, and microbial spoilage, all of which shorten shelf life and contribute to food waste. Lactose-free products, which often have reduced sugar content, are still considered niche and, as such, are sold at a premium, which deters many consumers from buying them and likely compels them to choose plant-based yogurt analogs, which are often marketed as more sustainable. The current trend toward increased use of direct-vat-set (DVS) cultures, which increases production costs and thus prices at the retailer, could likewise have this effect. In this review, we provide a comprehensive and industry-oriented analysis of existing and emerging strategies for achieving robust, sustainable, and cost-effective production of yogurt. We address industrial applicability, limitations, regulatory considerations, and future development potential. We argue that there is a current trend toward the use of more natural, bio-driven solutions for improving the properties of yogurt.
This study examines how public self-consciousness influences anticipatory avatar customization in Korean metaverse platform environments. In Study 1, 50 Korean university students created avatars under four conditions using iFland: free creation, private context, public context, and actual-self representation. Study 2 involved 100 independent raters evaluating the public suitability of freely created avatars. Results revealed that 96 percent created avatars differing from their actual appearance. Counterintuitively, individuals with higher public self-consciousness and agreeableness were significantly less likely to modify avatars for public contexts (p < 0.05). Study 2 confirmed that unmodified avatars were rated more suitable for public contexts (p < 0.05), suggesting that socially conscious individuals proactively incorporated appropriateness into initial designs. These preliminary findings suggest that Korean university students' cultural emphasis on social harmony may shape virtual identity through anticipatory rather than reactive customization, though cross-cultural replication with diverse samples is needed to establish the generalizability of these patterns.