Ratiometric fluorescence sensing and discrimination of tetracycline analogs by using coumarin-embedded Eu-MOF nanosensor.

As widely used antibiotics, tetracycline residues exist in food and environmental media, which pose certain hidden dangers and negative effects on public health. Therefore, the sensing and discrimination of tetracycline analogs (TCs) have great significance for improving food safety and preventing environmental pollution. Herein, a 7-hydroxycoumarin-3-carboxylic acid-embedded Eu-MOF (HC@Eu-MOF) material was constructed and then developed for the detection of TCs. Upon addition of TCs, the synthesized sensor displays opposite fluorescence changes at two different wavelengths due to the simultaneous presence of the inner filter effect (IFE) and the antenna effect (AE), and achieves a stable ratio signal response within 90 s. In addition, six important tetracycline analogs, including chlortetracycline (CTC), oxytetracycline (OTC), tetracycline (TC), metacycline (MC), doxycycline (DC) and demeclocycline (DMC) can be discriminated with 100 % accuracy through the principal component analysis even in extremely complicated mixtures. Further, a smartphone-assisted portable device was applied for visual sensing of TCs. The as-developed platform possessed the characteristics of simple synthesis, fast response, high sensitivity, and high stability, which further lays a further foundation for the on-site visual detection and discrimination of TCs in real samples.

Inflammatory Biomarker Reduction With Fostemsavir Over 96 Weeks in Heavily Treatment-Experienced Adults With Multidrug-Resistant HIV-1 in the BRIGHTE Study.

Background: Fostemsavir, a first-in-class attachment inhibitor that binds to the viral envelope protein gp120, is approved for heavily treatment-experienced persons with HIV-1 with limited treatment options. We explored changes in immunologic and coagulopathy parameters in the BRIGHTE study: a phase 3 trial that evaluated fostemsavir plus optimized background therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1. Methods: CD4+ T-cell count, CD4+/CD8+ ratio, soluble CD14, soluble CD163, and D-dimer levels were measured through 96 weeks in participants with 1 or 2 fully active antiretroviral agents available at screening. No formal statistical analyses were performed. Results: Among 272 participants, increases were observed from baseline to week 96 in CD4+ T-cell count (mean increase, +205 cells/mm3) and CD4+/CD8+ ratio (mean increase, +0.24). The proportion of observed participants with a CD4+/CD8+ ratio ≥0.45 increased from 9% (25/272) at baseline to 40% (85/213) at week 96. From baseline to week 96, we also observed trends toward decreases in the following (mean [SD] change): soluble CD14, -738.2 (981.8) µg/L; soluble CD163, -138.0 (193.4) µg/L; and D-dimer, -0.099 (0.521) mg/L fibrinogen-equivalent units. Decreases in biomarkers were generally observed among subgroups by baseline disease characteristics, virologic response, and CD4+ T-cell count. Conclusions: These data suggest that heavily treatment-experienced persons with multidrug-resistant HIV-1 treated with fostemsavir + optimized background therapy may have improvements in immune parameters, including markers of monocyte activation and coagulopathy. Clinical Trials Registration: NCT02362503 (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02362503).

Evaluation of Latent Tuberculosis Infection Using the ESAT6-CFP10 Skin Test Among International Freshmen With Diverse Skin Tones at a University - Nanjing City, Jiangsu Province, China, September 2023.

Introduction: Newer skin tests, including the ESAT6-CFP10 (EC) skin test, were recommended for diagnosing Mycobacterium tuberculosis (M. tb) infection. However, no data exist assessing the diagnostic performance of the EC skin test among foreign students with different skin tones. Methods: A cohort study at Nanjing Medical University screened incoming foreign freshmen. The EC skin test was used to assess for M. tb infection, and results were read at 24, 48, 72, and 96-hours post-administration. Results: Among 96 participants, M. tb infection rates at 24, 48, 72, and 96-hours post-injection were 3.13%, 7.29%, 13.54%, and 9.38%, respectively. While infection rates were lower among individuals with darker skin tones, the difference was not statistically significant (P=0.186), and variations were consistent across different measurement times. Trajectory analysis revealed 5.3% in the continuous-increasing group, 86.5% in the low-stable group, and 5.2% in the elevated-decreasing group. Notably, participants in the elevated-decreasing group had lighter skin tones, with trajectory patterns consistent across different skin colors. Discussion: The EC skin test is safe, and redness diameter is a more reliable indicator than induration. Results should be collected within 48 to 72 hours, with verification at 72 hours crucial if initial results are negative. Importantly, skin color does not affect EC skin test outcomes.

Enhancing Pelvic Floor Muscle Training Efficacy for Middle-Aged Women with Stress Urinary Incontinence Through Square Dance Integration: A Quasi-Experimental Study.

Background: Stress urinary incontinence (SUI) is effectively managed through pelvic floor muscle training (PFMT), yet poor adherence often undermines its efficacy. Given square dancing's popularity among middle-aged women, its integration with PFMT could potentially increase patient compliance. This study aims to investigate the impact of a hybrid program combining square dance and PFMT on SUI symptoms, quality of life, and treatment adherence in this demographic. Methods: Seventy-seven female participants from Luoyang were randomly allocated to an intervention group undergoing a 12-week program combining square dancing with PFMT, and two control groups receiving standard health advice or square dancing alone. Outcomes were assessed using subjective urinary incontinence rating, the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), and the Urinary Incontinence Quality of Life Scale (I-QOL), and a PFMT diary for compliance. Satisfaction was scored on a 10-point scale. Results: Participants (mean age: 53.35±5.11 years) did not differ significantly at baseline. Post-intervention, the intervention group showed significant improvements in SUI symptoms and quality of life compared to both control groups (P < 0.05), with higher compliance (96.54% vs 54.82% in control I) and satisfaction (8.86±0.85). Conclusion: Combining PFMT with square dancing significantly improved SUI symptoms, quality of life, and adherence among middle-aged women. Notably, despite the COVID-19 pandemic and associated restrictions during the 12-week intervention period, the communal and enjoyable nature of square dancing likely contributed to enhanced motivation and satisfaction.

The effect of matrine and glycyrrhizic acid on porcine reproductive and respiratory syndrome virus in Vitro and in vivo.

Porcine reproductive and respiratory syndrome (PRRS) is endemic worldwide, seriously affecting the development of the pig industry, but vaccines have limited protective effects against PRRSV transmission. The aim of this study was to identify potential anti-PRRSV drugs. We examined the cytotoxicity of seven compounds formulated based on the mass ratio of glycyrrhizic acid to matrine and calculated their inhibition rates against PRRSV in vitro. The results showed that the seven compounds all had direct killing and therapeutic effects on PRRSV, and the compounds inhibited PRRSV replication in a time- and dose-dependent manner. The compound with the strongest anti-PRRSV effect was selected for subsequent in vivo experiments. Pigs were divided into a control group and a medication group for the in vivo evaluation. The results showed that pigs treated with the 4:1 compound had 100% morbidity after PRRSV challenge, and the mortality rate reached 75% on the 8th day of the virus challenge. These results suggest that this compound has no practical anti-PRRSV effect in vivo and can actually accelerate the death of infected pigs. Next, we further analyzed the pigs that exhibited semiprotective effects following vaccination with the compound to determine whether the compound can synergize with the vaccine in vivo. The results indicated that pigs treated with the compound had higher mortality rates and more severe clinical reactions after PRRSV infection (p < 0.05). The levels of proinflammatory cytokines (IL-6, IL-8, IL-1ß, IFN-γ, and TNF-α) were significantly greater in the compound-treated pigs than in the positive control-treated pigs (p < 0.05), and there was no synergistic enhancement with the live attenuated PRRSV vaccine (p < 0.05). The compound enhanced the inflammatory response, prompted the body to produce excessive levels of inflammatory cytokines and caused body damage, preventing a therapeutic effect. In conclusion, the present study revealed that the in vitro effectiveness of these agents does not indicate that they are effective in vivo or useful for developing anti-PRRSV drugs. Our findings also showed that, to identify effective anti-PRRSV drugs, comprehensive drug screening is needed, for compounds with solid anti-inflammatory effects both in vitro and in vivo. Our study may aid in the development of new anti-PRRSV drugs.

Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.

Introduction: Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. Methods: The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192. Results: Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3. Conclusions: Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. Clinical trial number: NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Integrated Transcriptomic and Proteomic Characterization of a Chromosome Segment Substitution Line Reveals the Regulatory Mechanism Controlling the Seed Weight in Soybean.

Soybean is the major global source of edible oils and vegetable proteins. Seed size and weight are crucial traits determining the soybean yield. Understanding the molecular regulatory mechanism underlying the seed weight and size is helpful for improving soybean genetic breeding. The molecular regulatory pathways controlling the seed weight and size were investigated in this study. The 100-seed weight, seed length, seed width, and seed weight per plant of a chromosome segment substitution line (CSSL) R217 increased compared with those of its recurrent parent 'Suinong14' (SN14). Transcriptomic and proteomic analyses of R217 and SN14 were performed at the seed developmental stages S15 and S20. In total, 2643 differentially expressed genes (DEGs) and 208 differentially accumulated proteins (DAPs) were detected at S15, and 1943 DEGs and 1248 DAPs were detected at S20. Furthermore, integrated transcriptomic and proteomic analyses revealed that mitogen-activated protein kinase signaling and cell wall biosynthesis and modification were potential pathways associated with seed weight and size control. Finally, 59 candidate genes that might control seed weight and size were identified. Among them, 25 genes were located on the substituted segments of R217. Two critical pathways controlling seed weight were uncovered in our work. These findings provided new insights into the seed weight-related regulatory network in soybean.

Analysis of related factors for neuropsychiatric comorbidities in children with epilepsy.

OBJECTIVE: To analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy. METHOD: We randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis. RESULTS: There were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P < 0.05), while there were no statistically significant differences in age, gender, age of onset, form of onset, interictal epileptiform discharge, history of febrile convulsion, and the time from onset to initial visit (P > 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability. CONCLUSION: The course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.

Qudit-based high-dimensional controlled-not gate.

High-dimensional quantum systems expand quantum channel capacity and information storage space. By implementing high-dimensional quantum logic gates, the speed of quantum computing can be practically enhanced. We propose a deterministic 4 × 4-dimensional controlled-not (CNOT) gate for a hybrid system without ancillary qudits required, where the spatial and polarization states of a single photon serve as a control qudit of four dimensions, whereas two electron-spin states in nitrogen-vacancy (NV) centers act as a four-dimensional target qudit. As the control qudits are easily operated employing simple optical elements and the target qudits are available for storage, the CNOT gate works in a deterministic way, and it can be flexibly extended to n × n-dimensional (n > 4) quantum gates for other hybrid systems or different photonic degrees of freedoms. The efficiency and fidelity of the CNOT gate are analyzed aligning with current technological capabilities, finding that they have satisfactory performances.

Impact of Refractive Status on Presbyopia Progression among Patients with Presbyopia.

PURPOSE: To explore the impact of refractive status on presbyopia progression among patients with presbyopia. METHODS: This retrospective observational study included patients with presbyopia who visited the Seventh Affiliated Hospital of Sun Yat-sen University and Shenzhen Polytechnic Medical College between May 2018 and August 2022. The amplitude of accommodation (AMP) and near addition power (ADD) at 6 months and 1 year were collected. RESULTS: A total of 103 patients with presbyopia were included in this study: 42 patients with myopia, 23 patients with emmetropia, and 38 patients with hyperopia. There were significant differences in ΔAMP(6-month) and ΔADD(6-month) among patients with different refractive statuses, and the values of emmetropic patients and hyperopic patients were higher than in myopic patients (all P < 0.001). The ΔAMP(1-year) and ΔADD(1-year) of hyperopic patients were significantly higher than in emmetropic patients and myopic patients (all P < 0.001). The ΔADD(1-year) of emmetropic patients was greater than in myopic patients (P = 0.045), but there were no significant differences in ΔAMP(1-year) between patients with emmetropia and myopia (P = 0.090). CONCLUSIONS: The progression of presbyopia in hyperopic patients was relatively more significant than for emmetropia, followed by myopia. The prescription of presbyopia glasses might need to be replaced more frequently in patients with hyperopia.

Decoherence-free-subspace-based deterministic conversions for entangled states with heralded robust-fidelity quantum gates.

The decoherence-free subspace (DFS) serves as a protective shield against certain types of environmental noise, allowing the system to remain coherent for extended periods of time. In this paper, we propose two protocols, i.e., one converts two-logic-qubit Knill-Laflamme-Milburn (KLM) state to two-logic-qubit Bell states, and the other converts three-logic-qubit KLM state to three-logic-qubit Greenberger-Horne-Zeilinger states, through cavity-assisted interaction in DFS. Especially, our innovative protocols achieve their objectives in a heralded way, thus enhancing experimental accessibility. Moreover, single photon detectors are incorporated into the setup, which can predict potential failures and ensure seamless interaction between the nitrogen-vacancy center and photons. Rigorous analyses and evaluations of two schemes demonstrate their abilities to achieve near-unit fidelities in principle and exceptional efficiencies. Further, our protocols offer progressive solutions to the challenges posed by decoherence, providing a pathway towards practical quantum technologies.

N-aminomorpholine-functionalized bromine-doped carbon dots for hypochlorous acid detection in foods and imaging in live cells.

Hypochlorous acid (HClO) is used in food preservation. However, excessive HClO can deteriorate nutritional composition of food, compromise its quality, and potentially induce various diseases. Consequently, the development of multifunctional fluorescent probes for the sensitive and selective detection of HClO is highly anticipated for food safety. In this work, we designed a nanoprobe using N-aminomorpholine (AM)-functionalized bromine-doped carbon dots (Br-CDs-AM) for sensing HClO. This nanoprobe exhibits pH stability, strong resistance to photobleaching, superior long-term photostability (12 weeks), high sensitivity (19.3 nM), and an ultrarapid response (8 s) for detecting HClO residues in food matrices with percentage recovery (96.5 %-108 %) and RSDs less than 5.34 %. In addition, extremely low cytotoxicity and outstanding biocompatibility enable the nanoprobe to be used primarily for lysosome tracking and rapidly visualizing HClO in live cells. Thus, this study provides a new pathway to design unconventional nanoprobes for food safety assessment and subcellular organelle-specific imaging HClO.

Bismuth, Nitrogen-Codoped Carbon Dots as a Dual-Read Optical Sensing Platform for Highly Sensitive, Ultrarapid, Ratiometric Detection of Doxorubicin.

Doxorubicin (DOX) is a potent anticancer drug, but it has side effects on normal tissues, particularly myocardial cells. Therefore, it is crucial to detect the DOX concentration in body fluids for effective clinical treatment. In this work, N,Bi-codoped CDs (Bi,N-CDs) were synthesized through a one-step hydrothermal method to carbonize the raw materials of 2,4-dinitroaniline and bismuth nitrate. The resulting Bi,N-CDs showed a reduced emission at 490 nm and an enhanced emission at 590 nm in the presence of DOX. The ratio of fluorescence (FL) intensity (F590/F490) was found to be a reliable indicator of DOX concentration, ranging from 0.05 to 30 µM and 40-200 µM, with detection limits (LOD) of 34 and 24 nM, respectively. A ratiometric fluorescence nanoprobe was established for highly selective and sensitive detection of DOX using a specific electrostatic interaction and inner filter effect between Bi,N-CDs and DOX. Meanwhile, Bi,N-CDs exhibited a distinct color change ranging from yellow to orange-red when exposed to DOX, allowing for a colorimetric method to measure DOX levels in the range of 0.05-30 µM, with a detection limit of 169 nM. The probe was triumphantly used to monitor DOX in actual samples via a dual-mode optical sensing strategy. This study contributes to the development of heteroatom-doped CDs and expands their potential applications for detecting biological samples.

Synthetic strategies, properties and sensing application of multicolor carbon dots: recent advances and future challenges.

Recently, carbon dots (CDs) as newly developed carbon-based nanomaterials due to advantages such as excellent photostability and easy surface functionalization have generated wide application prospects in fields such as biological imaging and chemical sensing. The multicolor emission carbon dots (M-CDs) were acquired through the selection of different carbon source precursors, change of synthesis conditions and synthesis environment. Therefore, the aim of this review is to summarize the latest research progress in polychromatic CDs from the perspectives of synthesis strategies, luminescent mechanisms, luminescent properties and applications. This review focuses on how to prepare MCDs by changing raw materials and synthesis conditions such as reaction temperature, synthesis time, synthesis pH, and synthesis solvent. This review also presents the optical properties of MCDs, concentration effects, solvent effects, pH effects, elemental doping, and surface passivation on them, as well as their creative applications in the field of sensing applications. It is anticipated that this review will serve as a guide for the development of multifunctional M-CDs and inspire future research on controllable design and preparation of M-CDs.

Aggregation enhanced FRET: A simple but efficient strategy for the ratiometric detection of uranyl ion.

Uranium is one of the most important radionuclides but could also cause potential health risks to human beings due to its radioactive and chemical toxicity. It is an urgent task to develop a simple but efficient sensing platform for UO22+, the main existing form of uranium in environment. Herein, a rhodamine-functionalized carbon dots (o-CDs-Rho) was synthesized and applied for UO22+ sensing through a simple but novel aggregation-enhanced FRET strategy. The weak FRET efficiency (16.2%) of o-CDs-Rho in dispersed solution is significantly enhanced (>77.2%) after UO22+ triggered aggregation due to the increased number of rhodamine acceptors around each CDs from dispersed 80 to aggregated 2800. This is the first ratiometric fluorescence sensor with an inverse change of fluorescence intensity at dual emission wavelengths under single-wavelength excitation for UO22+. Under optimized experiment conditions, o-CDs-Rho nanosensor shows a low detection limit of 53 nM and excellent selectivity. Meanwhile, the as-prepared nanosensor also shows high reliability and stability. These excellent properties make it successful in detecting uranium content in real samples.

Sequence and expression regulation of the BCL2L2 gene in pigs.

B cell lymphoma-2-like 2 (BCL2L2), an important regulator of apoptosis, plays vital roles in several physiological processes, as revealed by studies in humans and mice. However, reports on pig BCL2L2 are few, and the encoding gene has not been identified experimentally. This study was designed to clone the porcine BCL2L2 gene and its alternative splicing (AS) transcripts using molecular biological techniques and to analyze the regulatory mechanisms underlying transcription and translation. The BCL2L2 cDNA (V1) was 807 bp in length and encoded a polypeptide of 193 aa containing four BCL-2 homology domains. A total of nine AS transcripts were obtained, among which V2 and V3 differed from V1 in the 5' untranslated region (UTR). The core promoter was mapped to a range of -1102 to -759 bp (the first nucleotide of the start codon was designated as +1). There were several functional cis-elements, including one SP1 and two C/EBPα binding sites at around -759 bp. AS in the 5' UTR is involved in the regulation of gene expression, as revealed by dual-luciferase reporter and western blot analysis, and the secondary structure of the 5' UTRs may be the reason for the differential expression of V1-3. At the same time, an upstream open reading frame (ORF) existed in each of the three 5' UTRs, was found to repress the expression of the main ORF. Additionally, the roles of porcine BCL2L2 in cell proliferation and apoptosis were preliminarily analyzed. The results will contribute to further characterizing the role of BCL2L2.

Nitrogen doped biomass derived carbon dots as a fluorescence dual-mode sensing platform for detection of tetracyclines in biological and food samples.

Nitrogen-doped carbon dots (N-CDs) were synthesized hydrothermally using abundantly accessible pitaya peel and 1,2-ethylenediamine as precursors. N-CDs exhibited favorable photostability, which can serve as a multifunctional nano-sensor for detection of three tetracycline antibiotics (TCs) based on fluorescence (FL) dual-mode sensing strategy. The FL intensity of N-CDs could be rapidly quenched by tetracycline (TC) and oxytetracycline (OTC) based on bandgap transition, inner filter effect (IFE), static quenching (SQ) and electrostatic interaction. While a new finding that FL of N-CDs demonstrated a remarkable enhancement in the presence of chlortetracycline (CTC) with the same detection mechanisms as TC and OTC, also including the aggregation-induced emission (AIE). Furthermore, an easily extensible fluorescence sensor array was developed based on multiple CDs for identifying multiple TCs in real samples. Therefore, the constructed N-CDs provides a new perspective for choosing extensive natural biomass to synthesize CDs, further developing a novel sensor to realize their versatile sensing application.

Erratum: A2780 human ovarian cancer cells with acquired paclitaxel resistance display cancer stem cell properties.

[This corrects the article DOI: 10.3892/ol.2013.1568.].

A novel carbon-nanodots-based theranostic nano-drug delivery system for mitochondria-targeted imaging and glutathione-activated delivering camptothecin.

Chemotherapy is severely limited by continuously decreased therapeutic efficacy and uncontrolled side effects on normal tissue, which can be improved by constructing a nanoparticle-based drug delivery system (DDS). Nevertheless, no studies have reported on DDS-based on carbon-nanodots (CNDs), combining subcellular organelle-targeted imaging/drug delivery, high drug loading content, and glutathione (GSH)-sensitive drug release into one system. Herein, the as-fabricated CNDs can be covalently conjugated with a mitochondria-targeting ligand (triphenylphosphine, TPP), a smart GSH-responsive disulfide linker (S-S), and the anticancer drug (camptothecin, CPT) to initially prepare a theranostic nano-DDS (TPP-CNDs-S-CPT) with the drug loading efficiency of 64.6 wt%. Owing to excellent water dispersibility, superior fluorescence properties, satisfactory cell permeability, and favorable biocompatibility, TPP-CNDs-S-CPT was successfully used for intracellular mitochondrial-targeted imaging in vitro. High intracellular GSH concentrations in tumor cells caused the cleavage of S-S, resulting in concomitant activation and release of CPT, as well as significant fluorescence enhancement. In vivo, TPP-CNDs-S-CPT exhibited lower biological toxicity and even higher tumor-activatable performance than free CPT, as well as specific cancer therapy with few side effects. The mitochondria-targeted ability and the precise drug-release in tumor make TPP-CNDs-S-CPT a hopeful chemotherapy prodrug, providing significant theoretical basis and data support for in-depth understanding and exploration of chemotherapeutic DDS-based on CNDs.

Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1.

In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).