Hierarchical Surface Pattern on Ni-Free Ti-Based Bulk Metallic Glass to Control Cell Interactions.

Ni-free Ti-based bulk metallic glasses (BMGs) are exciting materials for biomedical applications because of their outstanding biocompatibility and advantageous mechanical properties. The glassy nature of BMGs allows them to be shaped and patterned via thermoplastic forming (TPF). This work demonstrates the versatility of the TPF technique to create micro- and nano-patterns and hierarchical structures on Ti40Zr10Cu34Pd14Sn2 BMG. Particularly, a hierarchical structure fabricated by a two-step TPF process integrates 400 nm hexagonal close-packed protrusions on 2.5 µm square protuberances while preserving the advantageous mechanical properties from the as-cast material state. The correlations between thermal history, structure, and mechanical properties are explored. Regarding biocompatibility, Ti40Zr10Cu34Pd14Sn2 BMGs with four surface topographies (flat, micro-patterned, nano-patterned, and hierarchical-structured surfaces) are investigated using Saos-2 cell lines. Alamar Blue assay and live/dead analysis show that all tested surfaces have good cell proliferation and viability. Patterned surfaces are observed to promote the formation of longer filopodia on the edge of the cytoskeleton, leading to star-shaped and dendritic cell morphologies compared with the flat surface. In addition to potential implant applications, TPF-patterned Ti-BMGs enable a high level of order and design flexibility on the surface topography, expanding the available toolbox for studying cell behavior on rigid and ordered surfaces.

The golden tickets: impact of preference signaling on obstetrics and gynecology residency applicants.

BACKGROUND: With the residency selection process becoming more competitive and programs receiving unprecedented numbers of applications, some specialties have introduced preference signaling in an attempt to help applicants target programs of interest. In the 2022-2023 application cycle, obstetrics and gynecology also introduced a 2-tiered system with a limited number of gold signals (n=3) and silver signals (n=15). OBJECTIVE: Given the novelty of preference signaling in the obstetrics and gynecology residency application process, this study aimed to (1) assess the effect of signals on interview offers and match and (2) discuss applicant attitudes toward this preference signaling system. STUDY DESIGN: This was a voluntary cross-sectional survey study conducted in April 2023 that was open to all fourth-year medical students who applied to an obstetrics and gynecology residency in the United States. Self-reported demographics, signaling, interview, and match data were collected. In addition, students were asked about attitudes toward signaling on a 5-point Likert scale. RESULTS: Of the 1507 applicants who entered an obstetrics and gynecology residency via match or Supplemental Offer and Acceptance Program process, 969 (64.3%) completed the survey. Moreover, an additional 22 applicants who did not match responded to the survey. More respondents used all 3 gold tokens (98.3%) and all 15 silver tokens (94.3%). The mean number of applications sent was 74.3±35.1, and the mean number of interviews received per applicant was 12.8±6.6. The interviews or token yields were 64.0%±31.5% for gold tokens, 43.8%±23.1% for silver tokens, and 9.8%±10.0% for no token. Of the survey respondents, 340/951 (35.8%) matched to a gold token program, 338/951 (35.5%) matched to a silver token program, and 244/951 (25.7%) matched to a nontoken program. Furthermore, 499/951 applicants (52.5%) reported feeling slightly positive or very positive about signaling. CONCLUSION: Most obstetrics and gynecology applicants in this survey participated in preference signaling. Gold and silver tokens were associated with high ratios of interview invitations compared with no token. However, the overall number of applications did not decrease in the 2022-2023 cycle, and only half of survey respondents reported feeling positive about the signaling process. These results can inform program directors and students about application number and strategy in upcoming cycles.

Icotinib in a lung adenocarcinoma patient with acquired EGFR 19del/C797S mutation-mediated resistance to osimertinib: a case report.

Based on the FLAURA and AURA III trials, compared to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), osimertinib provides a longer overall survival benefit for patients with untreated EGFR mutated non-small cell lung cancer. Similar to other EGFR-TKIs, drug resistance is, however, inevitable. The most common mechanism of acquired resistance to first-line osimertinib therapy is the C797S mutation, which accounts for 6% of cases. In view of the current challenges of the development of the next generation of EGFR inhibitors, the mechanism of third-generation targeted drug resistances and targeted strategies are key for further exploration. Our case report discusses a female patient with advanced lung adenocarcinoma carrying the EGFR exon19 E746_A750delinsIP mutation who received osimertinib as first-line therapy and acquired C797S resistance during treatment. The patient was then treated with icotinib for 8 months until the disease progressed. Icotinib may be effective in patients with the EGFR 19del-C797S resistant mutation acquired after osimertinib treatment.

Clinical Guidelines on Compression Therapy in Venous Diseases.

BACKGROUND: In recent years, compression therapy has attracted gradually increasing clinical attention in lower extremity venous diseases. However, basic concepts and clear nomenclature, standard treatment methods, and consistent product standards for pressure equipment are lacking. Therefore, developing clinical guidelines for compression therapy is essential to improving the treatment of venous diseases. METHODS: Our panel generated strong (grade I), moderate (grade IIa and IIb), and weak (grade III) recommendations based on high-quality (class A), moderate-quality (class B), and low-quality (class C) evidence, using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach and the European Society of Cardiology (ESC) grading system. RESULTS: The panels made 30 recommendations from current evidence, focusing on 7 fields of lower extremity venous disease (venous thromboembolism, post-thrombotic syndrome (PTS), chronic venous insufficiency (CVI), varicose veins, hemangioma and vascular malformations, lymphedema, and venous ulcers) and 18 topics. CONCLUSIONS: Of the 30 recommendations made across the 18 topics, 7 were strong (grade I) and 17 were based on high-quality (class A) evidence, highlighting the need for further research of the use of compression therapy.

Taking the Express Lane: Student Attitudes Towards Tracking in Ob/Gyn Residency.

We sought to determine the subspecialty interests of fourth-year medical students (MS4s) matched to Ob/Gyn and evaluate their attitudes towards residency tracking. Matched MS4s completed a survey regarding subspecialization, confidence in that choice, and desire for tracking. A total of 922 MS4s completed the survey. Of these, 474 (51.4%) desired subspecialty training, but were less confident in their choice compared with those desiring generalist careers (60.0/100 vs. 64.9/100, P =0.003). Those seeking subspecialty training were more likely to desire tracking (15.2% vs. 39.5%, P <0.001). In conclusion, 51% of MS4s desired subspecialty training over generalist careers. Almost 40% of these students are interested in tracking.

Network pharmacology to unveil the mechanism of suanzaoren decoction in the treatment of alzheimer's with diabetes.

BACKGROUND: Suanzaoren Decoction (SZRD), a well-known formula from traditional Chinese medicine, has been shown to have reasonable cognitive effects while relaxing and alleviating insomnia. Several studies have demonstrated significant therapeutic effects of SZRD on diabetes and Alzheimer's disease (AD). However, the active ingredients and probable processes of SZRD in treating Alzheimer's with diabetes are unknown. This study aims to preliminarily elucidate the potential mechanisms and potential active ingredients of SZRD in the treatment of Alzheimer's with diabetes. METHODS: The main components and corresponding protein targets of SZRD were searched on the TCMSP database. Differential gene expression analysis for diabetes and Alzheimer's disease was conducted using the Gene Expression Omnibus database, with supplementation from OMIM and genecards databases for differentially expressed genes. The drug-compound-target-disease network was constructed using Cytoscape 3.8.0. Disease and SZRD targets were imported into the STRING database to construct a protein-protein interaction network. Further, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed on the intersection of genes. Molecular docking and molecular dynamics simulations were conducted on the Hub gene and active compounds. Gene Set Enrichment Analysis was performed to further analyze key genes. RESULTS: Through the Gene Expression Omnibus database, we obtained 1977 diabetes related genes and 622 AD related genes. Among drugs, diabetes and AD, 97 genes were identified. The drug-compound-target-disease network revealed that quercetin, kaempferol, licochalcone a, isorhamnetin, formononetin, and naringenin may be the core components exerting effects. PPI network analysis identified hub genes such as IL6, TNF, IL1B, CXCL8, IL10, CCL2, ICAM1, STAT3, and IL4. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that SZRD in the treatment of Alzheimer's with diabetes is mainly involved in biological processes such as response to drug, aging, response to xenobiotic, and enzyme binding; as well as signaling pathways such as Pathways in cancer, Chemical carcinogenesis - receptor activation, and Fluid shear stress and atherosclerosis. Molecular docking results showed that licochalcone a, isorhamnetin, kaempferol, quercetin, and formononetin have high affinity with CXCL8, IL1B, and CCL2. Molecular dynamics simulations also confirmed a strong interaction between CXCL8 and licochalcone a, isorhamnetin, and kaempferol. Gene Set Enrichment Analysis revealed that CXCL8, IL1B, and CCL2 have significant potential in diabetes. CONCLUSION: This study provides, for the first time, insights into the active ingredients and potential molecular mechanisms of SZRD in the treatment of Alzheimer's with diabetes, laying a theoretical foundation for future basic research.

GlycoTCFM: Glycoproteomics Based on Two Complementary Fragmentation Methods Reveals Distinctive O-Glycosylation in Human Sperm and Seminal Plasma.

Human semen, consisting of spermatozoa (sperm) and seminal plasma, represents a special clinical sample type in human body fluid. Protein glycosylation in sperm and seminal plasma plays key roles in spermatogenesis, maturation, capacitation, sperm-egg recognition, motility of sperm, and fertilization. In this study, we profiled the most comprehensive O-glycoproteome map of human sperm and seminal plasma using our recently presented Glycoproteomics based on Two Complementary Fragmentation Methods (GlycoTCFM). We showed that sperm and seminal plasma contain many novel and distinctive O-glycoproteins, which are mostly located in the extracellular region (seminal plasma) and sperm membrane, enriched in the biological processes of cell adhesion and angiogenesis, and mainly involved in multiple biological functions including extracellular matrix structural constituents and binding. Based on GlycoTCFM, we created a comprehensive human sperm and seminal plasma O-glycoprotein database that contains 371 intact O-glycopeptides and 202 O-glycosites from 68 O-glycoproteins. Interestingly, 105 manually confirmed O-glycosites from 25 O-glycoproteins were reported for the first time, and they were mainly modified by core 1 O-glycans. We also found that three highly abundant, highly complex, and highly O-glycosylated proteins (semenogelin-1, semenogelin-2, and equatorin) may play important roles in sperm or seminal plasma composition and function. These data deepen our knowledge about O-glycosylation in sperm and seminal plasma and lay the foundation for the functional study of O-glycoproteins in male infertility.

Evolution of 101 Apocynaceae plastomes and phylogenetic implications.

Apocynaceae are one of the ten species-richest angiosperm families. However, the backbone phylogeny of the family is yet less well supported, and the evolution of plastome structure has not been thoroughly studied for the whole family. Herein, a total of 101 complete plastomes including 35 newly sequenced, 24 reassembled from public raw data and the rest from the NCBI GenBank database, representing 26 of 27 tribes of Apocynaceae, were used for comparative plastome analysis. Phylogenetic analyses were conducted using a combined plastid data matrix of 77 protein-coding genes from 162 taxa, encompassing all tribes and 41 of 49 subtribes of Apocynaceae. Plastome lengths ranged from 150,897 bp in Apocynum venetum to 178,616 bp in Hoya exilis. Six types of boundaries between the inverted repeat (IR) regions and single copy (SC) regions were identified. Different sizes of IR expansion were found in three lineages, including Alyxieae, Ceropegieae and Marsdenieae, suggesting multiple expansion events of the IRs over the SC regions in Apocynaceae. The IR regions of Marsdenieae evolved in two ways: expansion towards the large single copy (LSC) region in Lygisma + Stephanotis + Ruehssia + Gymnema (Cosmopolitan clade), and expansion towards both LSC and small single copy (SSC) region in Dischidia-Hoya alliance and Marsdenia (Asia-Pacific clade). Six coding genes and five non-coding regions were identified as highly variable, including accD, ccsA-ndhD, clpP, matK, ndhF, ndhG-ndhI, trnG(GCC)-trnfM(CAU), trnH(GUG)-psbA, trnY(GUA)-trnE(UUC), ycf1, and ycf2. Maximum likelihood and Bayesian phylogenetic analyses resulted in nearly identical tree topologies and produced a well-resolved backbone comprising 15 consecutive dichotomies that subdivided Apocynaceae into 15 clades. The subfamily Periplocoideae were embedded in the Apocynoid grade and were sister to the Echiteae-Odontadenieae-Mesechiteae clade with high support values. Three tribes (Melodineae, Vinceae, and Willughbeieae), the subtribe Amphineuriinae, and four genera (Beaumontia, Ceropegia, Hoya, and Stephanotis) were not resolved as monophyletic. Our work sheds light on the backbone phylogenetic relationships in the family Apocynaceae and offers insights into the evolution of Apocynaceae plastomes using the most densely sampled plastome dataset to date.

Efficacy of CalliSpheres® microspheres versus conventional transarterial chemoembolization in the treatment of refractory colorectal cancer liver metastasis.

OBJECTIVE: CalliSpheres® is a microsphere that is already widely used for primary liver cancer treatment; however, its application in colorectal cancer liver metastasis (CRLM) is limited. The current study aimed to investigate the efficacy of CalliSpheres® drug-eluting bead (DEB) transarterial chemoembolization (TACE) therapy versus (vs.) conventional cTACE therapy in treating refractory CRLM (RCRLM) patients. METHODS: Twenty-two RCRLM patients who underwent CalliSpheres® DEB-TACE therapy (n = 11) or cTACE therapy (n = 11) were retrospectively analyzed. Data on clinical response, progression-free survival (PFS) and overall survival (OS) were retrieved. RESULTS: The objective response rate (36.4% vs. 18.2%, P = 0.338) and disease control rate (81.8% vs. 54.4%, P = 0.170) were both numerically (but not statistically) higher in the DEB-TACE group than in the cTACE group. Meanwhile, PFS was prolonged in the DEB-TACE group compared with the cTACE group [median: 12.0 (95% CI: 5.6-18.4) vs. 4.0 (95% CI: 0.9-7.1) months, P = 0.018]; OS was also longer in the DEB-TACE group compared with the cTACE group [median: 24.0 (95% CI: 18.3-29.7) vs. 14.0 (95% CI: 7.1-20.9) months, P = 0.040]. In addition, after adjustment by multivariate Cox analyses, DEB-TACE was superior to cTACE independently regarding PFS (HR: 0.110, 95% CI: 0.026-0.463, P = 0.003) and OS (HR: 0.126, 95% CI: 0.028-0.559, P = 0.006). CONCLUSION: CalliSpheres® DEB-TACE therapy may prolong survival profile than cTACE therapy in RCRLM patients, while further validation is still needed.

A randomized trial assessing the impact of educational podcasts on personal control and satisfaction during childbirth.

BACKGROUND: Childbirth education can help pregnant individuals feel in control, relieve anxiety and fear, and decrease pain perception. However, many barriers exist that impede patients from obtaining adequate childbirth education, especially in the era of the COVID-19 pandemic. Advances in technology, such as podcasts, can allow for asynchronous patient education. OBJECTIVE: This study aimed to assess the effect of a labor education podcast on personal perception of control and patient satisfaction during childbirth. STUDY DESIGN: This was a randomized controlled trial that included nulliparous, low-risk women with singleton gestations who reached 36 weeks' gestation at 2 academic hospitals in Philadelphia, Pennsylvania. Participants were randomized at 28 weeks and 0 days of gestation to usual education (control) or podcast education (intervention), which included links to 7 labor-related podcast episodes on patient-suggested topics that were available on widely-used podcatchers. Primary outcomes were assessed with a 3-question birth satisfaction survey and the Labour Agentry Scale to evaluate personal perception of control during childbirth. Secondary outcomes included the Edinburgh Postnatal Depression Scale score. Analyses were performed as intention-to-treat. Parametric and nonparametric data were compared using the Student t-test or Wilcoxon rank-sum test, as appropriate. RESULTS: A total of 201 women were randomized, and 153 were included in the final analysis (78 in podcast and 75 in control group). There were no significant differences in maternal demographics. Patients in the podcast group had higher median birth satisfaction scores compared with the control group (20 [18-21] vs 18 [16-21]; P=.002), without a significant difference in median Labour Agentry Scale scores (57 [50-63] vs 54 [47-62]; P=.12). When restricting analysis to patients who underwent induction, Labour Agentry Scale scores were significantly higher in the podcast group (58 [53-64] vs 54 [47-61]; P=.045), representing an increased perception of control. However, birth satisfaction score was not different between the groups (P=.06). The most downloaded podcasts were on induction and labor anesthesia. More than 95% of participants would recommend the podcasts to family and friends. CONCLUSION: An educational podcast on labor topics was well-received, increased patient satisfaction overall, and increased labor agentry among those who were induced. Podcasts are a promising educational modality to improve patient experience during childbirth, and warrant further exploration.

Effect of important modifiers on harmful effects in evidence synthesis practice of adverse events were insufficiently investigated: an empirical investigation.

BACKGROUND: Safety is important in the assessment of health interventions, while the results of adverse events are often susceptive to potential effect modifiers since the event risk tends to be rare. In this study, we investigated whether the potential impact of the important effect modifiers on harmful effects was analyzed in meta-analyses of adverse events. METHODS: Systematic reviews of healthcare interventions, had adverse events as the exclusive outcomes, had at least one meta-analysis, and published between 1st January 2015, and 1st January 2020 were collected. An adverse event was defined as any untoward medical occurrence in a patient or subject in healthcare practice. Six effect modifiers that are the most important for harmful effects were identified by a group discussion. The proportions of eligible systematic reviews that investigated the potential impact of the six effect modifiers on harmful effects were summarized. RESULTS: We identified 279 systematic reviews eligible for this study. Except for the modifier of interventions/controls (70.61%, 197/279), most of the systematic reviews failed to investigate the potential impact of treatment duration (21.15%, 59/279), dosage (24.73%, 69/279), age (11.47%, 32/279), risk of bias (6.45%, 18/279), and source of funding (1.08%, 3/279) on harmful effects. Systematic reviews with meta-analyses containing more studies were more likely to investigate the potential impacts of these modifiers on the effects, but the proportion was still low (2.3% to 33.3%). Systematic reviews that developed a protocol were significantly more likely to investigate the potential impact of all these effect modifiers (e.g. treatment duration: odds ratio = 5.08, 95% CI: 2.76 to 9.35) on the results. CONCLUSIONS: Current systematic reviews rarely investigated the potential impact of the important effect modifiers on harmful effects. Methodological guidelines for meta-analysis of adverse events should consider "effect modifier" as one of the domains to help systematic review authors better investigate harmful effects.

A tunable broadband terahertz MoS2 absorber using series-parallel hybrid network design.

A method for designing a broadband absorber using a series-parallel hybrid network is proposed. The performance of the broadband absorber is improved by using frequency-selective surface patterns based on a series-parallel hybrid equivalent circuit. The results indicate that the tunable single-layered terahertz MoS2 absorber has excellent broadband characteristics. Between 0.84 and 2.34 THz, the absorption and relative absorption bandwidth exceed 90% and 94.3%, respectively. Also, the absorption level can be adjusted from 90% to 10% by applying a bias voltage on the electrodes. The effects of different types of MoS2 layers and surface fluctuations in monolayered MoS2 on the properties of the absorber are demonstrated. In the 60° (TM) and 50° (TE) ranges, the polarization of the terahertz absorber is insensitive to the incidence angle. Overall, this method enables the single-layered absorber to exhibit excellent broadband characteristics comparable to those of multilayered structures, as well as simplifies the structure. Consequently, this method significantly broadens the usefulness of tunable single-layered absorbers for radar stealth, terahertz imaging, and electrically tunable modulation.

Commercially Available Prenatal Vitamins Do Not Meet American College of Obstetricians and Gynecologists Nutritional Guidelines.

OBJECTIVE: This study aimed to evaluate the reported amount of the American College of Obstetricians and Gynecologists (ACOG) recommended nutrients in commercially available, over-the-counter prenatal vitamins (PNVs) in the United States, to assess their adequacy compared with the ACOG guidelines, and to compare these supplements by cost. STUDY DESIGN: The top 30 online Amazon and Google shopping items found using "prenatal vitamins" in September 2022 were included for analysis if they included the words "prenatal" and "vitamin" in the label and contained multiple nutrients. Duplicates between Amazon and Google were excluded as well as vitamins that did not list all ingredients. The reported amounts of 11 key nutrients, as recommended by the ACOG, for each product were recorded, as well as supplemental form and cost per 30-day supply. A cost analysis was done of PNVs that met the ACOG recommendations for the highlighted nutrients compared with those that did not. Five out of the 11 key nutrients (folic acid, iron, docosahexaenoic acid, vitamin D, and calcium) were specifically highlighted, as deficiencies in these nutrients are known to correlate with significant clinical outcomes in pregnancy. RESULTS: A total of 48 unique PNVs were included for final analysis. Of these PNVs, none were compliant with suggested amounts of all five key vitamins and nutrients. No products met daily recommendations for calcium. Only five PNVs were compliant with recommendations with ⅘ key nutrients. Of note, 27% of PNVs did not have the recommended amount of folic acid (13/48). The median cost of PNVs that were not compliant with the four nutrients mentioned above was $18.99 (interquartile range [IQR]: $10.00-$30.29), which was not statistically different from the median cost of the PNVs that did meet compliance with the four nutrients, which was $18.16 (IQR: $9.13-$26.99), p = 0.55. CONCLUSION: There were significant variations in the level of nutrients and cost of commercially available, over-the-counter PNVs in the United States. This raises concern that there should be more regulation of PNVs. KEY POINTS: · Commercially available over the counter PNVs vary in their content of the ACOG recommended nutrients and vitamins for pregnancy.. · None of these studied PNVs contain adequate amounts of all five key nutrients.. · Cost is not correlated with more compliance with the ACOG recommendations..

Selenium Atom-Polarization Effect Determines TrxR-Specific Recognition of Metallodrugs.

Thioredoxin reductase (TrxR) is highly overexpressed in cancer cells to promote malignant tumor survival. Designing drugs that inhibit TrxR activity is a promising approach to achieve highly effective cancer chemotherapy. However, the selectivity of TrxR inhibitors continue to be a challenge for scientists. In this work, we demonstrate a new strategy to selectively inhibit TrxR through constructing electrophilic center -N-Se(δ+)-N- by using the polarization effect of the selenium atom. The constructed electrophilic center interacts noncovalently with the active motif of TrxR to avoid the interference of other residues in human tissues, thereby selectively inhibiting intracellular TrxR activity. Computational and experimental analysis confirms that the formed electrophilic selenium center preferred to attack the SeC residues in the redox active center of TrxR at the 498 site through strong noncovalent interactions. Both in vitro and in vivo experimental results confirmed that this strategy can significantly improve the anticancer effect. This study may provide a novel route to design highly effective and selective chemotherapeutic drugs.

Design, synthesis, and preclinical evaluation of a novel bifunctional macrocyclic chelator for theranostics of cancers.

PURPOSE: This study was to design and synthesize a novel bifunctional chelator, named Dar, primarily validated by conjugating to tumor targeting motifs, labeled with radiometals, and performed preclinical evaluation of tumor imaging and cancer therapy in murine tumor models. METHOD: The designed Dar was synthesized and characterized by X-ray crystallography, 1H/13C NMR, and mass spectrometry. Dar-PSMA-617 was conjugated and radiolabeled with 68Ga, 177Lu, and 89Zr. The in vivo behavior of 68 Ga/89Zr-labeled Dar-PSMA-617 were evaluated using micro-PET imaging and biodistribution from image quantitation and tissue radioactivity counting, with 68Ga/89Zr-labeled NOTA/DOTA/DFO-PSMA-617 analogs as controls, respectively. The [177Lu]-Dar-PSMA-617, with [177Lu]-DOTA-PSMA-617 as control, was evaluated in competitive cell uptake, tumor cell internalization, and efflux studies. The treatment efficacy of [177Lu]Lu-Dar-PSMA-617, with [177Lu]Lu-DOTA-PSMA-617 as control, was evaluated in PSMA-positive LNCaP tumor-bearing mice. In addition, the ability of Dar for radiolabeling nanobody was tested by conjugating Dar to KN035 nanobody. The resultant [89Zr]Zr-Dar-KN035 nanobody, with [89Zr]Zr-DFO-KN035 as control, was evaluated by micro-PET imaging and biodistribution in a mouse model bearing MC38&MC38-hPD-L1 colon cancer. RESULTS: 68Ga, 89Zr, and 177Lu-radiolabeled Dar-PSMA-617 complexes were able to be produced under mild condition with high radiochemical yield and purity successfully. [177Lu]Lu-Dar-PSMA-617 had higher cellular uptake yet similar internalization and efflux properties in LNCaP cells, as compared to [177Lu]Lu-DOTA-PSMA-617. Micro-PET images demonstrated significantly higher tumor uptake of [68Ga]Ga-Dar-PSMA-617, than that of the analog [68Ga]Ga-DOTA-PSMA-617. The tumor uptake values of [68Ga]Ga-Dar-PSMA-617 at multiple time points are comparable to that of [68Ga]Ga-NOTA-PSMA-617, although a higher and persistently prolonged kidney retention was resulted in during the study period. The Dar chelator can also successfully mediate the radiolabeling with 89Zr, while the resultant [89Zr]Zr-Dar-PSMA-617 demonstrated a similar biodistribution with [89Zr]Zr-DFO-PSMA-617 measured at 96 h p.i. The treatment with [177Lu]Lu-Dar-PSMA-617 significantly inhibited the tumor growth, showing much better efficacy than that of [177Lu]Lu-DOTA-PSMA-617 at the same injected radioactivity and mass dose. Dar was covalently linked to KN035 nanobody and enabled radiolabeling with 89Zr in high yield and radiochemical purity at room temperature. The resultant [89Zr]Zr-Dar-KN035, with [89Zr]Zr-DFO-KN035 as control, demonstrated superior tumor uptake and detection capability in PET imaging studies. CONCLUSION: The Dar, as a novel bifunctional chelator for medicating the labeling of radiometals onto tumor targeting carriers, was successfully synthesized and chemically characterized. Test radiolabeling, on PSMA-617 and a nanobody as tool targeting molecule carriers, demonstrated the Dar has potential as a universal bifunctional chelator for radiolabeling various radiometals (at least 68Ga, 177Lu, and 89Zr tested) commonly used for clinical imaging and therapy. Using a novel Dar chelator results in altered in vivo behavior of the carriers even though labeled with the same nuclide. This capability makes Dar an alternative to the existing choices for radiolabeling new carrier molecules with various radiometals, especially the radiometals with large radius.

FATE: The Effect of Fetal Antenatal Testing Education on Patient Knowledge and Satisfaction.

OBJECTIVE: This study aimed to evaluate the effect of a physician-created educational infographic on the knowledge and attitudes of patients undergoing antenatal fetal surveillance. STUDY DESIGN: This single-center prospective cohort study evaluated the impact of implementing an electronic educational infographic about antenatal fetal surveillance. English-speaking women receiving antenatal surveillance between the ages of 18 to 50 years were approached for inclusion. The preimplementation group enrolled women receiving antenatal surveillance between March 8, 2021, and April 2, 2021, who received usual care. Postimplementation, from April 5 to May 6, 2021, patients at our site received the infographic about antenatal fetal surveillance at their first antenatal testing appointment. Both pre- and postimplementation groups received a 5-question multiple-choice knowledge and 12-question attitude survey between 320/7 to 336/7 weeks at baseline (prior to receipt of infographic in postimplementation group) and again between 350/7 to 366/7 weeks. Patients were included in the analysis only if they completed both surveys. Differences from initial to final survey were compared between groups. RESULTS: Of 106 patients who completed the initial survey, 74 (69.8%) participants finished both surveys (preimplementation = 39 and postimplementation = 35). There were no significant differences in demographics between the two groups, including in baseline knowledge (p = 0.58) or attitude tests (p = 0.57). There was no significant difference in knowledge on final surveys between groups (p = 0.79). However, utilization of the infographic was associated with a significant increase in attitude survey score from initial to final survey in the postimplementation group as compared with usual care (median difference: pre = 0, interquartile rang [IQR]: [-1 to +4] vs. post = +3, IQR: [+1 to +6], p = 0.016). CONCLUSION: A physician-created infographic on antepartum fetal testing was associated with overall improved patient attitude toward fetal testing, showing that small education interventions can increase patient satisfaction with care. KEY POINTS: · A physician-created, readable, and patient-oriented education resource is feasible.. · Infographic patient-education materials do not change patient knowledge about antenatal testing.. · Infographic patient-education materials can improve patient attitude toward antenatal testing..

Microspheres present comparable efficacy and safety profiles compared with polyvinyl alcohol for bronchial artery embolization treatment in hemoptysis patients.

BACKGROUND: The present study aimed to compare the efficacy and safety profiles of microspheres versus (vs.) polyvinyl alcohol (PVA) for bronchial artery embolization (BAE) treatment in patients with hemoptysis. METHODS: Totally, 152 patients with hemoptysis who were about to receive BAE treatment were consecutively enrolled and divided into microspheres group (N = 62) and PVA group (N = 90). Technical success and clinical success were assessed after BAE procedure, and the hemoptysis-recurrence status, survival status and adverse events were recorded during follow-up. RESULTS: Technical success rates were both 100% in microspheres group and PVA group; clinical success rate (96.8% vs. 100.0%, P = 0.165), 6-month (9.7% vs. 7.8%, P = 0.681) and 1-year (9.7% vs. 8.9%, P = 0.869) hemoptysis recurrence rate, 6-month (4.8% vs. 2.2%, P = 0.374) and 1-year (4.8% vs. 3.3%, P = 0.639) mortality were similar between microspheres group and PVA group. Furthermore, hemoptysis-free survival (P = 0.488) and overall survival (P = 0.321) were of no difference between two groups. In addition, all adverse events were mild, and there was no difference of adverse events between two groups (all P > 0.05). These data were validated by further multivariate regression analysis. CONCLUSIONS: Microspheres present comparable efficacy and safety profiles compared with PVA for the BAE treatment in patients with hemoptysis, providing evidence for embolic agent selection.

Structural and functional insights into the unique CBS-CP12 fusion protein family in cyanobacteria.

Cyanobacteria are important photosynthetic organisms inhabiting a range of dynamic environments. This phylum is distinctive among photosynthetic organisms in containing genes encoding uncharacterized cystathionine ß-synthase (CBS)-chloroplast protein (CP12) fusion proteins. These consist of two domains, each recognized as stand-alone photosynthetic regulators with different functions described in cyanobacteria (CP12) and plants (CP12 and CBSX). Here we show that CBS-CP12 fusion proteins are encoded in distinct gene neighborhoods, several unrelated to photosynthesis. Most frequently, CBS-CP12 genes are in a gene cluster with thioredoxin A (TrxA), which is prevalent in bloom-forming, marine symbiotic, and benthic mat cyanobacteria. Focusing on a CBS-CP12 from Microcystis aeruginosa PCC 7806 encoded in a gene cluster with TrxA, we reveal that the domain fusion led to the formation of a hexameric protein. We show that the CP12 domain is essential for hexamerization and contains an ordered, previously structurally uncharacterized N-terminal region. We provide evidence that CBS-CP12, while combining properties of both regulatory domains, behaves different from CP12 and plant CBSX. It does not form a ternary complex with phosphoribulokinase (PRK) and glyceraldehyde-3-phosphate dehydrogenase. Instead, CBS-CP12 decreases the activity of PRK in an AMP-dependent manner. We propose that the novel domain architecture and oligomeric state of CBS-CP12 expand its regulatory function beyond those of CP12 in cyanobacteria.

Development of a novel anti-liver fibrosis formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis.

CONTEXT: Xiaoyaosan decoction (XYS), a classical Traditional Chinese Medicine (TCM) formula is used to treat liver fibrosis in clinics. OBJECTIVE: This study explores defined compound combinations from XYS decoction to treat liver fibrosis. MATERIALS AND METHODS: Network pharmacology combined with transcriptomics analysis was used to analyze the XYS decoction and liver depression and spleen deficiency syndrome liver fibrosis. From the constructed XYS-Syndrome-liver fibrosis network, the top 10 active formulas were developed by topological analysis according to network stability. The most active formula was determined by in vitro study. The anti-fibrosis effect was evaluated by in vitro and in vivo studies. RESULTS: According to the network XYS-Syndrome-liver fibrosis network, 8 key compounds and 255 combinations were predicted from in XYS. Luteolin, licochalcone A, aloe-emodin and acacetin formula (LLAAF) had a synergistic effect on the proliferation inhibition of hepatic stellate cells compared to individual compounds alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rats. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signalling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signalling in vitro and in vivo. CONCLUSIONS: This study developed a novel anti-liver formula LLAAF from XYS, and demonstrated its anti-liver fibrotic activity which may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signalling.

Hyperglycemia-induced cardiomyocyte death is mediated by lysosomal membrane injury and aberrant expression of cathepsin D.

Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Previous studies have shown an association between lysosomal dysfunction and diabetic heart injury. The present study examined if mimicking hyperglycemia in cultured cardiomyocytes could induce lysosomal membrane permeabilization (LMP), leading to the release of lysosome enzymes and subsequent cell death. High glucose (HG) reduced the number of lysosomes with acidic pH as shown by a fluorescent pH indicator. Also, HG induced lysosomal membrane injury as shown by an accumulation of Galectin3-RFP puncta, which was accompanied by the leakage of cathepsin D (CTSD), an aspartic protease that normally resides within the lysosomal lumen. Furthermore, CTSD expression was increased in HG-cultured cardiomyocytes and in the hearts of 2 mouse models of type 1 diabetes. Either CTSD knockdown with siRNA or inhibition of CTSD activity by pepstatin A markedly diminished HG-induced cardiomyocyte death, while CTSD overexpression exaggerated HG-induced cell death. Together, these results suggested that HG increased CTSD expression, induced LMP and triggered CTSD release from the lysosomes, which collectively contributed to HG-induced cardiomyocyte injury.