Substantial Uptake Research Articles

Safety and biomarker assessment of ST316, a novel peptide antagonist of ß-catenin, in patients with advanced solid tumors.

286 Background: Constitutive activation of ß-catenin, resulting in its nuclear accumulation and deregulated transcriptional activity, is a key event in colorectal cancer (CRC). Additionally, pathway mutations correlate with immune exclusion in CRC and across different tumor types. Disruption of the interaction of ß-catenin and its co-activator BCL9 is sufficient to suppress oncogenic ß-catenin transcriptional activity, without impacting its homeostatic functions in normal tissue. ST316 is a first-in-class, cell-penetrating peptide antagonist of the ß-catenin and BCL9 interaction. Preclinical evaluation revealed significant bioavailability and potent activity in CRC models with no impact on ß-catenin homeostatic functions such as intestinal stem cell survival or bone morphology. Methods: A phase 1-2 (P1-2) escalation-expansion study has enrolled patients (pts) with advanced solid tumors likely to harbor abnormalities in the Wnt/ß-catenin pathway, to assess the safety, pharmacokinetics (PK), biomarker and preliminary activity of ST316, and to recommend a P2 dose (RP2D). Paired biopsies were collected when feasible and assessed for drug penetration and pharmacodynamic biomarkers. Peripheral blood (PB) collected pre- and post-treatment was assessed by flow cytometry for polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Results: As of Sep.24, 2024; 23 pts with CRC (N=14), NSCLC (N=4), PDAC (N=2), or Breast and Ovarian cancer (N=1, each), were treated in 6 cohorts (0.5-12mg/kg) with IV ST316, once weekly. Treatment related AEs were observed in 17/23 pts and were mostly low grade, except for 2 G3 AEs that resolved: Fatigue (1) and ALT/AST elevation (1). No dose-limiting toxicities (DLTs) were observed. Single agent ST316 showed disease stabilization in 4 pts. PK analysis showed dose-proportional increases in Cmax and AUC for doses up to 8 mg/kg. IHC analysis showed substantial tumor penetration of ST316 in all analyzed samples and evidence of a treatment-induced redistribution of β-catenin in a subset of pts. PB analysis indicated high baseline levels of the ß-catenin-driven immunosuppressive PMN-MDSCs , followed by a significant decrease after ST316 exposure (p<0.005). The RP2D selected for combination cohorts in CRC is 8mg/kg; additional PD assessments are ongoing. Conclusions: Monotherapy ST316 was well-tolerated with dose-proportional PK and substantial tumor uptake. Pharmacodynamic analyses demonstrate mechanistic evidence of antagonism of ß-catenin signaling, including redistribution of ß-catenin subcellular localization and significant depletion of the ß-catenin-driven immunosuppressive PMN-MDSC population. Based on these data, ST316 advanced into P2 in CRC pts in combination with SoC in 2 nd and 3 rd line. Clinical trial information: NCT05848739 .

Tracking Immunity: An Increased Number of COVID-19 Boosters Increases the Longevity of Anti-RBD and Anti-RBD-Neutralizing Antibodies.

Since the World Health Organization declared COVID-19 a pandemic in March 2020, the virus has caused multiple waves of infection globally. Arizona State University (ASU), the largest four-year university in the United States, offers a uniquely diverse setting for assessing immunity within a large community. This study aimed to test our hypothesis that an increased number of exposures to SARS-CoV-2 RBD through vaccination/boosters/infection will increase SARS-CoV-2 antibody seroprevalence by increasing the longevity of anti-RBD and anti-RBD-neutralizing antibodies. A serosurvey was conducted at ASU from 30 January to 3 February 2023. Participants completed questionnaires about demographics, respiratory infection history, symptoms, and COVID-19 vaccination status. Blood samples were analyzed for anti-receptor binding domain (RBD) IgG and anti-nucleocapsid (NC) antibodies, offering a comprehensive view of immunity from both natural infection and vaccination. The seroprevalence of anti-RBD IgG antibodies was 96.2% (95% CI: 94.8-97.2%), and 64.9% (95% CI: 61.9-67.8%) of participants had anti-NC antibodies. Anti-RBD IgG levels correlated strongly with neutralizing antibody levels, and participants who received more vaccine doses showed higher levels of both anti-RBD IgG and neutralizing antibodies. Increasing the number of exposures through vaccination and/or infection resulted in higher and long-lasting antibodies. The high levels of anti-RBD antibodies observed reflect substantial vaccine uptake within this population. Ongoing vaccination efforts, especially as new variants emerge, are essential to maintaining protective antibody levels. These findings underscore the importance of sustained public health initiatives to support broad-based immunity and protection.

Synergistic antiviral potential of N-(2-hydroxy)propyl-3-trimethylammoniumchitosan-functionalized silver nanoparticles with oseltamivir against influenza a viruses

This study introduced a novel antiviral approach by combining three substances with different antiviral mechanisms: N-(2-hydroxy)propyl-3-trimethylammoniumchitosan (HTC), silver nanoparticles (AgNPs), and oseltamivir. First, positively surface-charged AgNPs were prepared using an environmentally friendly method. The surfaces of these AgNPs were capped with cationic quaternary chitosan HTC. It exhibits a positive zeta potential with extraordinary stability in aqueous solutions and facilitates substantial and rapid cellular uptake including entry into the cell nucleus. HTC-AgNPs display broad-spectrum antiviral activity against three influenza A viruses (H5N1, H3N2, and H1N1) at biocompatible concentrations. When blended with oseltamivir, HTC-AgNPs enhances the antiviral activity from that of oseltamivir alone by at least 20 times. After 24 h of combined treatment, the inhibition efficiency against influenza A virus can attain up to 99.9 %. We anticipate that this combination could reduce the effective dose of Tamiflu by 10-fold when used in clinic, thus shortening recovery period and lowering the medication costs. Moreover, the synergistic effects of the three active substances would reduce the likelihood of the emergence of drug-resistant viral strains. This would, in turn, enhance the effectiveness and safety of this medication.

Mucoadhesive Enhancement of Gelatine by Tannic Acid Crosslinking for Buccal Application

ABSTRACTThis study aims to evaluate the impact of formulation parameters on tannic acid‐crosslinked gelatine (GelTA) films, intended as a mucoadhesive matrix for extended buccal drug delivery. GelTA films were prepared using the solvent evaporation technique and screened based on their mucoadhesive and dissolution characteristics. The formulation variables included the source of gelatine (bovine and fish), tannic acid concentration, pH of the film‐forming solutions, and the type and concentration of plasticisers. Subsequently, selected films underwent further characterisation (e.g., crosslinking density, stability) to elucidate their features as a drug delivery matrix. GelTA films exhibited a significantly improved dissolution time compared to the non‐crosslinked film (BG‐GLY20), while maintaining a substantial water uptake capacity conducive to a matrix system with extended action. The bovine GelTA film containing 5% w/w tannic acid and 20% w/w glycerine, prepared at pH 7 (BG‐GLY20‐7), exhibited a 1.6‐fold increase in mucoadhesivity and an extended dissolution time of up to 6 h compared to BG‐GLY20 (control), along with superior antioxidant and antimicrobial properties. However, stability studies indicate the need for an oxygen‐free environment for film storage. In conclusion, GelTA films show promise as a buccal film matrix, offering extended dissolution times, substantial water uptake, and enhanced adhesive strength.

Health, beliefs, and faith: HPV vaccine uptake intent among Catholic, Evangelical, and mainline protestant parents

ABSTRACT The HPV vaccine has the potential to prevent nearly 92% of HPV-related cancer cases, yet its uptake remains suboptimal. While well-documented barriers to HPV vaccine uptake include inadequate knowledge and lack of provider recommendation, religious preferences have emerged as another crucial factor influencing vaccination decisions. This study examined the interrelatedness of religion, beliefs, and HPV vaccination uptake among children among Catholic, Evangelical, and Mainline Protestant parents. A nationally representative survey was conducted among 1,068 U.S. parents from one of three major Christian denominations: Catholic, Evangelical, or Mainline Protestant. We examined the extent to which demographic factors, constructs from the Health Belief Model (perceived severity, susceptibility, benefits, barriers, self-efficacy, and cues to action), and faith-based support variables contributed to HPV vaccination decisions among parents from the specified religious denominations. Among the surveyed parents, 72.3% indicated that their child had received the HPV vaccine, revealing a substantial but incomplete uptake rate. Notably, no statistically significant differences were observed in vaccination rates across the three denominational groups. Perceived HPV vaccine benefits (p < .001), perceived barriers (p < .001) and perceived self-efficacy (p = .013) were strongly associated. Parents reporting that their child’s healthcare provider asked them about the vaccine (p < .001) and those more receptive to faith-based support for HPV vaccination (p = .049) were more likely to report child HPV vaccine uptake. To enhance HPV vaccine uptake among the examined religious denominations, strengthening provider-parent communication regarding the HPV vaccine and fostering partnerships between healthcare providers and supportive religious congregations can serve as powerful levers for promoting vaccination acceptance and compliance.

Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer

BackgroundPeritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach — leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) — can minimize off-target toxicity related to TAT, often associated with full-length antibodies. We hypothesized that a pretargeting strategy could effectively treat high-grade serous (HGS) ovarian tumors while minimizing toxicity. MethodsWe utilized the humanized antibody, AR9.6, labeled with actinium-225 (225Ac). AR9.6 targets fully glycosylated and hypoglycosylated isoforms of MUC16. For biodistribution and radioimmunotherapy studies, AR9.6-TCO was injected into OVCAR3-bearing mice 72 h before administering [225Ac]Ac-mcp-PEG8-Tz, e.g. using a 1,2,4,5-tetrazine conjugated to the macropa chelator via a polyethylene glycol (PEG) linker. ResultsBiodistribution data revealed that the pretargeting approach achieved substantial tumor uptake. Cerenkov luminescence imaging confirmed successful in vivo pretargeting during TAT studies. Compared to the control groups, TAT with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz significantly suppressed tumor growth and improved overall survival in OVCAR3 tumor-bearing mice. Renal and ovarian pathology compatible with toxicity was observed in mice in addition to transient hematologic toxicity. ConclusionWe confirmed that pretargeting with AR9.6-TCO and [225Ac]Ac-mcp-PEG8-Tz has durable antitumor effects in high MUC16-expressing tumors. These findings demonstrate great potential for using pretargeting in combination with TAT for the treatment of ovarian cancer. ClassificationBiological Sciences; Applied Biological Sciences.

Extracellular Phosphate Modulation and Polyphosphate Accumulation by Corynebacterium matruchotii and Streptococcus mutans.

(1) Background: An alternative and understudied microbial mechanism that may influence demineralization is the microbially mediated ion exchange of Ca2+ and orthophosphate (Pi), which alters the saturation state of the mineral species within the surface enamel. There is a need to examine the ability of members of the oral microbiome to modulate Ca2+ and Pi, which control mineral solubility, in order to effectively evaluate mineralization therapies to improve oral health. (2) Methods: Pi uptake was measured using an ascorbic acid assay during a BHI liquid culture growth of Corynebacterium matruchotii and Streptococcus mutans for up to 20 h. The initial and endpoint medium Ca2+ levels were measured using ICP-OES. Bacterial cells were examined at different growth stages using DAPI/polyP binding emission at 525 nm to detect the presence of internalized macromolecules of polyphosphates (polyP) that could drive Pi uptake. (3) Results: C. matruchotii (p = 0.0061) substantially accumulated Pi (3.84 mmol/L), with a concomitant formation of polyP. In contrast, S. mutans did not take up Pi or accumulate polyP. No significant Ca2+ drawdown in the media was observed in either strain. (4) Conclusions: This study suggests that when examining the future efficacy of prevention technologies to improve, in vitro assays may consider including specific oral bacteria capable of substantial Pi uptake.

COMPARATIVE EFFICACY OF SLICED TRAGAL CARTILAGE VERSUS TEMPORALIS FASCIA IN TYMPANOPLASTY: A STUDY ON HEARING IMPROVEMENT AND GRAFT UPTAKE

Objective: Chronic suppurative otitis media (CSOM) often necessitates surgical intervention, with tympanoplasty being a key procedure to restore hearing. The choice of graft material-sliced tragal cartilage versus temporalis fascia remains controversial due to potential differences in acoustic transmission and graft resilience. Methods: This prospective cohort study included 48 patients with CSOM, randomly assigned to receive either tragal cartilage or temporalis fascia grafts. Outcomes measured were hearing improvement and graft uptake, assessed through audiometric testing and otoscopic evaluations. Results: Both groups showed significant improvements in hearing postoperatively, with no statistically significant difference in hearing gain (P=0.3064). Graft uptake rates were comparable, with a non-significant lower reperforation rate in the cartilage group (P=0.551). Conclusion: The study supports the use of either sliced tragal cartilage or temporalis fascia as effective materials for tympanoplasty, offering substantial hearing improvement and reliable graft uptake.

Access to affordable daycare and women's mental health in Rajasthan, India: Evidence from a cluster-randomised social intervention.

Women in India are often responsible for unpaid household work, family caregiving, and paid work, which can contribute to poorer mental health. The provision of childcare has the potential to improve women's mental health, but evidence on the effects of providing access to daycare is limited. We designed a cluster-randomised trial and used data from a sample of 2858 mothers with age-eligible children from 160 village hamlets in rural Rajasthan, India, to evaluate the impact of providing access to a community-based daycare programme on social and emotional aspects of women's mental health. We conducted a baseline survey in early 2016, randomised hamlets to intervention or control groups approximately six months later, and delivered the final post-intervention survey approximately two years thereafter. Treatment assignment increased the probability that a respondent used a daycare over the two-year follow-up by 40.9 percentage points. Providing randomised access to a daycare resulted in 0.2 (95% confidence interval (CI) = -0.1, 0.4) fewer symptoms of mental distress, representing a 9.5% decline compared to the baseline mean of 2.1 symptoms, as well as a 3.7 (95% CI = -0.8, 8.3) percentage point increase in the proportion of women who reported feeling very happy, equivalent to an 11.0% increase relative to the baseline mean of 33.6%. Among social indicators, treatment assignment was associated with a 5.6 (95% CI = -1.2, 12.4) percentage point increase in membership in an association, a relative increase of 43.4% compared to the baseline mean of 12.9%. The intervention did not have an appreciable impact on measures of life satisfaction or trust in institutions. Two-stage least squares instrumental variable analyses showed that daycare use decreased mental distress by 0.4 (95% CI = -0.1, 0.8) symptoms, increased the proportion of women who were very happy by 9.4 (95% CI = 0.0, 17.6) percentage points, and increased membership in an organisation by 15.9 (95% CI = 8.4, 23.7) percentage points. The provision of affordable, community-based daycare was associated with substantial uptake and showed potential for improving mothers' mental health in a rural context where most women were not employed in the formal labour force. ISRCTN clinical trial registry (ISRCTN45369145), registered on 16 May 2016; American Economic Association's registry for randomised controlled trials (AEARCTR-0000774), registered on 15 July 2015.

Cardiac Structure and Function of Elite Australian Jockeys Compared to the General Population: An Observational Cross-Sectional Study.

Research highlights the intense physiological demands of thoroughbred racing on jockeys, with elevated heart rates and substantial oxygen uptake, confirming the rigorous physical nature of the sport, however, the cardiovascular changes resulting from the physical demands of thoroughbred racing remain unexplored in Australian jockeys. Therefore, the objective of this study was to compare measures of cardiac structure and function of professional Australian jockeys to that of the general population and to determine if there are differences in heart structure and function detected using echocardiography. Forty-six jockeys and thirty-three participants from the general population underwent two-dimensional echocardiography, which included all standard views and measurements. Each measurement was compared between groups using a Mann-Whitney U test. Groups were matched for age (jockeys (35 ± 12 years) and controls (36 ± 13 years)). Jockeys were shorter (1.64 ± 0.07m vs. 1.75 ± 0.09m, p < 0.001), lighter (56.5 ± 6.0kg vs. 74.2 ± 12.9kg, p < 0.001) and had a lower body surface area (BSA) (1.55 ± 0.17m2 vs.1.9 ± 0.2m2, p < 0.001). Jockeys had a larger absolute left ventricular (LV) end diastolic volume than the control group (120 ± 18.2ml vs.109.3 ± 29.0ml, p = 0.05) which had a larger variation when indexed for BSA (78.0 ± 12.2 ml/m2 vs. 57.5 ± 13.3 ml/m2, p < 0.001). Jockeys demonstrated a higher LV mass index (79.4 ± 18.1g/m2 vs. 64.2 ± 15.4g/m2, p < 0.001). Left atrial volume index was larger in jockeys (33.4 ± 6.5mL/m2 vs. 26.3 ± 7.0mL/m2, p < 0.001). There were no differences in global longitudinal strain (GLS) for either group overall (-19.3 ± 3.0% vs. -19.8 ± 1.6%, p = 0.52), but 17% of the jockey group demonstrated an abnormal GLS. Jockeys have adaptations to their cardiac structure and function compared to the general population. Differences could be attributed to chronic physiological demands of racing and should be considered in future research involving jockeys.

A bacterial cellulose composite separator with high thermal stability and flame retardancy for high-performance lithium ion batteries

Separators play a crucial role in enhancing the safety of lithium-ion batteries (LIBs); however, commercial polyolefin separators exhibit poor thermal stability and are flammable. This study investigates the use of green, environmentally friendly, and renewable bacterial cellulose as a substrate for developing a composite separator (BHM/5). The BHM/5 separator, comprising bacterial cellulose, an inorganic mineral nano-hydroxyapatite (HAP) and flame-retardant melamine polyphosphate (MPP), is fabricated via freeze drying and high-temperature pressing. The developed composite separator demonstrates superior thermal stability and excellent flame retardancy compared with commercial polyolefin separators while maintaining structural integrity at 200 °C and exhibiting self-extinguishing properties after ignition. Furthermore, the BHM/5 separator exhibits a high porosity of 74 % and a substantial electrolyte uptake of 459 %, achieving an ion conductivity of 1.44 mS/cm. As a result, the cell of the LiFePO4-Li system assembled demonstrates an initial discharge capacity of 131.35 mAh·g−1 at a current density of 1C and a capacity retention of 95.4 % after 150 cycles.

Enhancing precision targeting of ovarian cancer tumor cells in vivo through extracellular vesicle engineering.

Extracellular vesicles (EVs) function as natural mediators of intercellular communication, secreted by cells to facilitate cell-cell signaling. Due to their low toxicity, immunogenicity, biodegradability, and potential to encapsulate therapeutic drugs, EVs hold significant therapeutic promise. Nevertheless, their limited targeting ability often diminishes their therapeutic impact. Therefore, enhancing EVs by incorporating targeting units onto their membranes could bolster their targeting capabilities, enabling them to accumulate in specific cells and tissues. In this study, we engineered EVs to fuse ephrin-B2 with the EV membrane protein LAMP2b. This modification aimed to direct the engineered EVs toward the ephrin-B4 receptor expressed on the surface of ovarian cancer cells. The engineered EVs retained their inherent properties, including size, expression of EV membrane proteins, and morphology, upon isolation. In vitro experiments using real-time imaging revealed that EVs engineered with the ephrin-B2 ligand exhibited substantial internalization and uptake by ovarian cancer cells, in stark contrast to native EVs. In vivo, the engineered EVs carrying the ephrin-B2 ligand effectively targeted ovarian cancer cells, surpassing the targeting efficiency of control EVs. This innovative approach establishes a novel targeting system, enhancing the uptake of EVs by ovarian cancer cells. Our findings underscore the potential of using EVs to target cancer cells, thereby enhancing the effectiveness of anti-cancer therapies while minimizing off-target effects and toxicity in normal cells and organs.

“Pink power”—the importance of coralline algal beds in the oceanic carbon cycle

Current evidence suggests that macroalgal-dominated habitats are important contributors to the oceanic carbon cycle, though the role of those formed by calcifiers remains controversial. Globally distributed coralline algal beds, built by pink coloured rhodoliths and maerl, cover extensive coastal shelf areas of the planet, but scarce information on their productivity, net carbon flux dynamics and carbonate deposits hampers assessing their contribution to the overall oceanic carbon cycle. Here, our data, covering large bathymetrical (2–51 m) and geographical ranges (53°N–27°S), show that coralline algal beds are highly productive habitats that can express substantial carbon uptake rates (28–1347 g C m−2 day−1), which vary in function of light availability and species composition and exceed reported estimates for other major macroalgal habitats. This high productivity, together with their substantial carbonate deposits (0.4–38 kilotons), renders coralline algal beds as highly relevant contributors to the present and future oceanic carbon cycle.

Substantial CO2 uptake by biomass ashes under natural condition in China

A considerable amount of biomass ashes, resulting from agricultural waste field burning, wildfire, and solid biofuel incineration, is typically discarded in field or stored in dumps, where the alkaline oxides (CaO, MgO) they contain undergo carbonation and weathering-erosion processes over extended periods, continuously absorbing CO2 from the atmosphere and soil. However, their CO2 absorption behavior under natural conditions remains insufficiently explored in China. Using life cycle assessment (LCA) and material flow analysis (MFA) methods, this study developed a CO2 absorption analysis model for biomass ashes under natural conditions. We estimated the CO2 absorption of 9 different types of biomass ash from 1950 to 2022 through Monte Carlo uncertainty simulation. The results show that biomass ashes in China absorbed approximately 24.17Mt/year (95 % CI, 11.10–43.56) of CO2 under nature conditions, with the annual average CO2 uptake showing a steady increase from 1950 to 2022. The total CO2 uptake reached 856.85Mt (95 % CI, 368.73–1526.01) over these decades, mainly due to the significant contribution of biomass ash produced by domestic straw burning and fuelwood combustion, which accounted for 51.97 % and 22.08 %, respectively. Our findings highlight the substantial carbon sink benefits of biomass ash, providing valuable insights for further studies on carbon cycles in natural ecosystems and the potential integration of biomass ash in Carbon Capture, Utilization, and Storage (CCUS) technologies.

Polyphosphate-Mediated Crystallographic and Colloidal Stabilization of CuS Nanoparticles: Enhanced NIR-Responsive Chemo-Photothermal Efficacy.

Photothermal therapy (PTT) is an emerging treatment modality for cancer management. However, the photothermal agents (PTAs) used in PTT should have sufficient biocompatibility, water dispersibility, and good photoresponsive. In this aspect, water-dispersible and biocompatible linear polyphosphate (LP)-functionalized CuS nanoparticles (LP-CuS NPs) were developed using sodium tripolyphosphate (LP molecule) as a surface passivating agent. The successful formation of the green covellite CuS phase was confirmed by X-ray diffraction and TEM analyses, and its surface functionalization with the LP ligand was evident from X-ray photoelectron spectroscopy, Fourier transform infrared, thermogravimetric analysis, and light scattering measurements. It has been found that the use of LP not only stabilizes the crystallographic covellite CuS phase by overcoming the requirement of a soft ligand but also provides long-term aqueous colloidal stability, which is essential for PTT applications. The aqueous suspension of LP-CuS NPs showed excellent heating efficacy under near infrared (NIR) light irradiation (980 nm) and has a strong binding affinity towards anticancer drug, doxorubicin hydrochloride (DOX). The drug-loaded systems (DOX@LP-CuS NPs) revealed a pH-dependent drug release behavior with higher concentrations in a mild acidic environment. The in vitro studies showed substantial cellular uptake of DOX-loaded systems in cancer cell lines and enhanced toxicity towards them upon irradiation of NIR light through apoptotic induction, suggesting their potential application in chemo-photothermal therapy.

Green Nanotechnology Through Papain Nanoparticles: Preclinical in vitro and in vivo Evaluation of Imaging Triple-Negative Breast Tumors.

Recent advancements in nanomedicine and nanotechnology have expanded the scope of multifunctional nanostructures, offering innovative solutions for targeted drug delivery and diagnostic agents in oncology and nuclear medicine. Nanoparticles, particularly those derived from natural sources, hold immense potential in overcoming biological barriers to enhance therapeutic efficacy and diagnostic accuracy. Papain, a natural plant protease derived from Carica papaya, emerges as a promising candidate for green nanotechnology-based applications due to its diverse medicinal properties, including anticancer properties. This study presents a novel approach in nanomedicine and oncology, exploring the potential of green nanotechnology by developing and evaluating technetium-99m radiolabeled papain nanoparticles (99mTc-P-NPs) for imaging breast tumors. The study aimed to investigate the efficacy and specificity of these nanoparticles in breast cancer models through preclinical in vitro and in vivo assessments. Papain nanoparticles (P-NPs) were synthesized using a radiation-driven method and underwent thorough characterization, including size, surface morphology, surface charge, and cytotoxicity assessment. Subsequently, P-NPs were radiolabeled with technetium-99m (99mTc), and in vitro and in vivo studies were conducted to evaluate cellular uptake at tumor sites, along with biodistribution, SPECT/CT imaging, autoradiography, and immunohistochemistry assays, using breast cancer models. The synthesized P-NPs exhibited a size mean diameter of 9.3 ± 1.9 nm and a spherical shape. The in vitro cytotoxic activity of native papain and P-NPs showed low cytotoxicity in HUVEC, MDA-MB231, and 4T1 cells. The achieved radiochemical yield was 94.2 ± 3.1% that were sufficiently stable (≥90%) for 6 h. The tumor uptake achieved in the 4T1 model was 2.49 ± 0.32% IA/g at 2h and 1.51 ± 0.20% IA/g at 6h. In the spontaneous breast cancer model, 1.19 ± 0.20% IA/g at 2h and 0.86 ± 0.31% IA/g at 6h. SPECT/CT imaging has shown substantial tumor uptake of the new nanoradiopharmaceutical and clear tumor visualization. 99mTc-P-NPs exhibited a high affinity to tumoral cells confirmed by ex vivo autoradiography and immunohistochemistry assays. The findings underscore the potential of green nanotechnology-driven papain nanoparticles as promising agents for molecular imaging of breast and other tumors through SPECT/CT imaging. The results represent a substantial step forward in the application of papain nanoparticles as carriers of diagnostic and therapeutic radionuclides to deliver diagnostic/therapeutic payloads site-specifically to tumor sites for the development of a new generation of nanoradiopharmaceuticals.

Metagenomic and isotopic insights into carbon fixation by autotrophic microorganisms in a petroleum hydrocarbon impacted red clay aquifer

Autotrophic microorganisms, the pivotal carbon fixers, exhibit a broad distribution across diverse environments, playing critical roles in the process of carbon sequestration. However, insights into their distribution characteristics in aquifers, particularly in those petroleum-hydrocarbon-contaminated (PHC) aquifers that were known for rich in heterotrophs, have been limited. In the study, groundwater samples were collected from red clay aquifers in the storage tank leakage area of a PHC site, a prevalent aquifer type in southern China and other regions. Metagenomics combined with hydrochemical and inorganic carbon isotope analyses were employed to elucidate the presence of microbial carbon fixation and its driving forces. Results showed that there were hundreds of autotrophic microorganisms participating in distinct carbon fixation processes in the red clay PHC aquifers. Reductive tricarboxylic acid (rTCA) and dicarboxylate/4-hydroxybutyrate (DC/4HB), as well as 3-hydroxypropionate (3HP or/and 3-hydroxypropionate/4-hydroxybutyrate (3HP/4HB)) were the predominant carbon fixation pathways. The abundances of carbon fixation genes and autotrophic microorganisms were significantly and positively correlated with hydrocarbon concentrations and δ13C of dissolved inorganic carbon (δ13C-DIC) values. This finding indicated that the petroleum hydrocarbon significantly promoted the proliferation of carbon fixation microorganisms, leading to a substantial uptake of inorganic carbon. Therefore, we deduce that this process holds considerable potential for carbon sequestration in PHC-contaminated aquifers.

How Internal Medicine Clerkship Directors Are Using Entrustable Professional Activities: A National Survey Study.

In the present assessment environment in undergraduate medical education at U.S. medical schools, the prevalence and implementation of Entrustable Professional Activities (EPAs) in internal medicine (IM) clerkships are not well understood. To describe the prevalence and approach to EPA use in U.S. IM clerkships. Cross-sectional, nationally representative survey of core IM clerkship directors. One-hundred forty IM clerkship directors at Liaison Committee on Medical Education-accredited U.S./U.S. territory-based allopathic medical schools with membership in the Clerkship Directors in Internal Medicine (CDIM) as of December 2022. Use of EPAs in IM core clerkships, including use for grading, types of EPAs, use of supportive measures for assessment, and current validity frameworks. The survey response was 80% (112/140); two additional respondents completed the section on EPA use (n = 114). Approximately half of respondents (47%) reported their IM clerkship used EPAs. Among schools accredited after 1977, a higher percentage was associated with having incorporated EPAs (p = 0.03). The Association of American Medical Colleges Core EPAs for Entering Residency (CEPAER) was the most common framework used by Clerkship Directors (CDs) for developing EPAs (55%). Most CDs (56%) used EPAs for both formative and summative assessments, and approximately half of CDs (48%) used EPAs for a portion of the final grade determination. CDs who used EPAs were no more likely to report efforts to ensure the validity of assessment, the use of faculty development, or that written assessments were a valid measure of students' performance compared to those who did not use EPAs. Although EPAs have experienced substantial uptake in the IM clerkship and contribute to formative and summative assessment of learners, their use does not appear to be associated with enhanced efforts to obtain validity information.

Bovine serum albumin as a nanocarrier for efficient encapsulation of hydrophobic garcinol-A strategy for modifying the in vitro drug release kinetics

Garcinia indica, known as kokum, has been extensively researched for its therapeutic potential. Among the wide variety of phytoconstituents, garcinol is the most efficacious, holding anti-inflammatory, anti-cancer, and anti-diabetic properties. Hydrophobicity and a certain level of toxicity have constrained the drug's application and necessitated a modified dosage form design. The drug has been well explored in the form of extracts but bears very limited application in dosage forms. These prompted in implementation of protein polymers, due to non-toxicity, biocompatibility, and biodegradability. BSA encapsulates the drug, by the desolvation method. The unavailability of past exploration of garcinol with protein polymer accelerated the novelty of this study, to improve the solubility and bioavailability of the drug, modify the drug release kinetics, and ascertain the effectiveness of the NPs to combat inflammation in-vitro. NPs were characterized and satisfactory outcomes were retrieved in terms of all characterizations. The drug release studies depicted a sustained release of up to 85 % over 16 h, ensuring that garcinol can be modulated to give a desired scale of modified release. In vitro cellular uptake studies suggested a substantial uptake of NPs in cell lines and its effectiveness to mitigate inflammation was affirmed by in-vitro anti-inflammatory studies, using ELISA.

Quantitative Three-Dimensional Imaging Analysis of HfO2 Nanoparticles in Single Cells via Deep Learning Aided X-ray Nano-Computed Tomography.

It is crucial for understanding mechanisms of drug action to quantify the three-dimensional (3D) drug distribution within a single cell at nanoscale resolution. Yet it remains a great challenge due to limited lateral resolution, detection sensitivities, and reconstruction problems. The preferable method is using X-ray nano-computed tomography (Nano-CT) to observe and analyze drug distribution within cells, but it is time-consuming, requiring specialized expertise, and often subjective, particularly with ultrasmall metal nanoparticles (NPs). Furthermore, the accuracy of batch data analysis through conventional processing methods remains uncertain. In this study, we used radioenhancer ultrasmall HfO2 nanoparticles as a model to develop a modular and automated deep learning aided Nano-CT method for the localization quantitative analysis of ultrasmall metal NPs uptake in cancer cells. We have established an ultrasmall objects segmentation method for 3D Nano-CT images in single cells, which can highly sensitively analyze minute NPs and even ultrasmall NPs in single cells. We also constructed a localization quantitative analysis method, which may accurately segment the intracellularly bioavailable particles from those of the extracellular space and intracellular components and NPs. The high bioavailability of HfO2 NPs in tumor cells from deeper penetration in tumor tissue and higher tumor intracellular uptake provide mechanistic insight into HfO2 NPs as advanced radioenhancers in the combination of quantitative subcellular image analysis with the therapeutic effects of NPs on 3D tumor spheroids and breast cancer. Our findings unveil the substantial uptake rate and subcellular quantification of HfO2 NPs by the human breast cancer cell line (MCF-7). This revelation explicates the notable efficacy and safety profile of HfO2 NPs in tumor treatment. These findings demonstrate that this 3D imaging technique promoted by the deep learning algorithm has the potential to provide localization quantitative information about the 3D distributions of specific molecules at the nanoscale level. This study provides an approach for exploring the subcellular quantitative analysis of NPs in single cells, offering a valuable quantitative imaging tool for minute amounts or ultrasmall NPs.