Application of fluorocarbon nanoparticles of 131I-fulvestrant as a targeted radiation drug for endocrine therapy on human breast cancer.

BACKGROUND: Breast cancer is the most prevalent malignant tumor among women, with hormone receptor-positive cases constituting 70%. Fulvestrant, an antagonist for these receptors, is utilized for advanced metastatic hormone receptor-positive breast cancer. Yet, its inhibitory effect on tumor cells is not strong, and it lacks direct cytotoxicity. Consequently, there's a significant challenge in preventing recurrence and metastasis once cancer cells develop resistance to fulvestrant. METHOD: To address these challenges, we engineered tumor-targeting nanoparticles termed 131I-fulvestrant-ALA-PFP-FA-NPs. This involved labeling fulvestrant with 131I to create 131I-fulvestrant. Subsequently, we incorporated the 131I-fulvestrant and 5-aminolevulinic acid (ALA) into fluorocarbon nanoparticles with folate as the targeting agent. This design facilitates a tri-modal therapeutic approach-endocrine therapy, radiotherapy, and PDT for estrogen receptor-positive breast cancer. RESULTS: Our in vivo and in vitro tests showed that the drug-laden nanoparticles effectively zeroed in on tumors. This targeting efficiency was corroborated using SPECT-CT imaging, confocal microscopy, and small animal fluorescence imaging. The 131I-fulvestrant-ALA-PFP-FA-NPs maintained stability and showcased potent antitumor capabilities due to the synergism of endocrine therapy, radiotherapy, and CR-PDT. Throughout the treatment duration, we detected no notable irregularities in hematological, biochemical, or histological evaluations. CONCLUSION: We've pioneered a nanoparticle system loaded with radioactive isotope 131I, endocrine therapeutic agents, and a photosensitizer precursor. This system offers a combined modality of radiotherapy, endocrine treatment, and PDT for breast cancer.

The critical role of calcineurin/NFAT (C/N) pathways and effective antitumor prospect for colorectal cancers.

Transcription factors (TFs) like a nuclear factor of activated T-cells (NFAT) and its controller calcineurin are highly expressed in primary intestinal epithelial cells (IECs) due to delamination, damage by tumor-associated flora and selective activation in the intestinal tract tumor are crucial in the progression and growth of colorectal cancer (CRC). This study sought to summarize the current findings concerning the dysregulated calcineurin/NFAT (C/N) signaling involved in CRC initiation and progression. These signalings include proliferation, T-cell functions, and glycolysis with high lactate production that remodels the acidosis, which genes in tumor cells provide an evolutionary advantage, or even increased their attack phenotype. Moreover, the relationship between C/N and gut microbiome in CRC, especially role of NFAT and toll-like receptor signaling in regulating intestinal microbiota are also discussed. Furthermore, this review will discuss the proteins and genes relating to C/N induced acidosis in CRC, which includes ASIC2 regulated C/N1 and TFs associated with the glycolytic by-product that affect T-cell functions and CRC cell growth. It is revealed that calcineurin or NFAT targeting to antitumor, selective calcineurin inhibition or targets in NFAT signaling may be useful for clinical treatment of CRC. This can further aid in the identification of specific targets via cancer patient-personalized approach. Future studies should be focused on targeting to C/N or TLR signaling by the combination of therapeutic agents to regulate T-cell functions and gut microbiome for activating potent anticancer property with the prospect of potentiating the antitumor therapy for CRC.

Genome-Wide Identification, Expression Analysis, and Subcellular Localization of Carthamus tinctorius bHLH Transcription Factors.

The basic helix-loop-helix (bHLH) family is the second largest superfamily of transcription factors that belongs to all three eukaryotic kingdoms. The key function of this superfamily is the regulation of growth and developmental mechanisms in plants. However, the bHLH gene family in Carthamus tinctorius has not yet been studied. Here, we identified 41 bHLH genes in Carthamus tinctorius that were classified into 23 subgroups. Further, we conducted a phylogenetic analysis and identified 10 conserved protein motifs found in the safflower bHLH family. We comprehensively analyzed a group of bHLH genes that could be associated with flavonoid biosynthesis in safflower by gene expression analysis, gene ontology annotation, protein interaction network prediction, subcellular localization of the candidate CtbHLH40 gene, and real-time quantitative expression analysis. This study provides genome-wide identification of the genes related to biochemical and physiological processes in safflower.

Cardiac support device (ASD) delivers bone marrow stem cells repetitively to epicardium has promising curative effects in advanced heart failure.

Ventricular restraint therapy is a non-transplant surgical option for the management of advanced heart failure (HF). To augment the therapeutic applications, it is hypothesized that ASD shows remarkable capabilities not only in delivering stem cells but also in dilated ventricles. Male SD rats were divided into four groups (n = 6): normal, HF, HF + ASD, and HF + ASD-BMSCs respectively. HF was developed by left anterior descending (LAD) coronary artery ligation in all groups except normal group. Post-infarcted electrocardiography (ECG) and brain natriuretic peptide (BNP) showed abnormal heart function in all model groups and HF + ASD-BMSCs group showed significant improvement as compared to other HF, HF + ASD groups on day 30. Masson's trichrome staining was used to study the histology, and a large blue fibrotic area has been observed in HF and HF + ASD groups and quantification of fibrosis was assessed. ASD-treated rats showed normal heart rhythm, demonstrated by smooth -ST and asymmetrical T-wave. The mechanical function of the heart such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and heart rate was brought to normal when treated with ASD-BMSCs. This effect was more prominent than that of ASD therapy alone. In comparison to HF group, the SD rats in HF + ASD-BMBCs group showed a significant decline in BNP levels. So ASD can deliver BMSCs to the cardiomyocytes successfully and broaden the therapeutic efficacy, in comparison to the restraint device alone. An effective methodology to manage the end-stage HF has been proved.

Evaluation of cerebral hemodynamics by computed tomography perfusion imaging before and after cranioplasty in patients with brain injury.

OBJECTIVE: To assess the clinical significance of computed tomography perfusion (CTP) imaging by evaluating cerebral hemodynamic changes quantitatively and qualitatively both before and after cranioplasty in patients with brain injury. METHODS: Sixteen patients with cerebral trauma underwent CTP imaging 2 days before and 10-15 days after cranioplasty. The cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time and time to peak were analysed in both the affected and corresponding contralateral regions, including the basal ganglia, thalamus, cortex and white matter. Quantitative analyses were performed before and after cranioplasty. RESULTS: The CBF in the cortex of the affected side was significantly increased after cranioplasty (p < 0.05), while that in the white matter on the affected side was slightly lower than that on the contralateral side (p < 0.05). The CBV in the corresponding contralateral area of the basal ganglia decreased post-cranioplasty (p < 0.05). No other difference in blood flow parameters was found between the two sides before or after cranioplasty. CONCLUSION: CTP imaging can accurately reflect changes in cerebral hemodynamics before and after cranioplasty in patients with trauma. Cranioplasty can significantly improve CBF in the cortex on the affected side for a short time (10-15 days) to meet the prevailing metabolic demand.

Antiviral Nucleotide Incorporation by Recombinant Human Mitochondrial RNA Polymerase Is Predictive of Increased In Vivo Mitochondrial Toxicity Risk.

Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the in vitro pharmacology of compound 1, a monophosphate prodrug of a 2'-ethynyluridine developed for the treatment of HCV. Compound 1 inhibits multiple HCV genotypes in vitro (50% effective concentration [EC50], 0.05 to 0.1 µM) with a selectivity index of >300 (50% cytotoxic concentration [CC50], 30 µM in MT-4 cells). The active triphosphate metabolite of compound 1, compound 2, does not inhibit human α, ß, or γ DNA polymerases but was a substrate for incorporation by the human mitochondrial RNA polymerase (POLRMT). In dog, the oral administration of compound 1 resulted in elevated serum liver enzymes and microscopic changes in the liver. Transmission electron microscopy showed significant mitochondrial swelling and lipid accumulation in hepatocytes. Gene expression analysis revealed dose-proportional gene signature changes linked to loss of hepatic function and increased mitochondrial dysfunction. The potential of in vivo toxicity through mitochondrial polymerase incorporation by nucleoside analogs has been previously shown. This study shows that even moderate levels of nucleotide analog incorporation by POLRMT increase the risk of in vivo mitochondrial dysfunction. Based on these results, further development of compound 1 as an anti-HCV compound was terminated.

Single nucleotide polymorphisms of nucleotide excision repair and homologous recombination repair pathways and their role in the risk of osteosarcoma.

OBJECTIVE: To evaluate the influence of polymorphisms in nucleotide excision repair (NER) and homologous recombination repair (HRR) pathways on the development of osteosarcoma patients. METHODS: Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. RESULTS: Total 148 osteosarcoma patients and 296 control subjects were collected from Taizhou First People's Hospital. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were significantly associated with increased risk of osteosarcoma, and the ORs(95%CI) were 1.58(1.03-2.41) and 2.66(1.73-4.08), respectively. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, with ORs(95%CI) of 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively. CONCLUSION: Our results suggest that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with an increased risk for osteosarcoma, which suggests that NER and HRR pathways modulate the risk of developing osteosarcoma.

The glucose metabolic frame of conditions induce the overproduction of a co-culture pigment: induction mechanism of the pigment and development of a specific eutrophic-oligotrophic transition cultivation system.

Induction mechanism of a potential red pigment (RPc) was investigated in the present paper. A typical competition relationship exists between Penicillium sp. HSD07B and Candida tropicalis during co-culture, and C. tropicalis converts glucose into glycerol, organic acids and other substances, resulting in a stricter glucose limitation and the secretion of RPc. Moreover, a novel eutrophic-oligotrophic transition cultivation system (E-OTCS) was developed to produce red pigment during monoculture of Penicillium sp. HSD07B. However, the monoculture pigment (RPm) is different from RPc in components, and RP3 and RP4 only occur in RPm when glycerol is supplied. In addition, the additions of glycerol and organic acids to glucose exhaustion medium can significantly improve the pigment yield. These facts not only prove the feasibility of producing RPm using E-OTCS, but also reveal that, besides glucose exhaustion, the accumulation of metabolites of glucose including glycerol and organic acids is also an important factor influencing the production of RPc.

Sequence and phylogenetic analysis of H7N3 avian influenza viruses isolated from poultry in China in 2011.

Four H7N3 avian influenza viruses (AIVs) were isolated from domestic ducks in live-poultry markets in Zhejiang Province, Eastern China, in 2011. All viruses were characterized by whole-genome sequencing with subsequent phylogenetic analysis and genetic comparison. Phylogenetic analysis of all eight viral genes showed that the viruses clustered in the Eurasian lineage of influenza viruses. The hemagglutinin cleavage site of all viruses indicated that the four strains were low-pathogenic avian influenza viruses.

Characterization of a highly pathogenic H5N1 avian influenza virus isolated from ducks in Eastern China in 2011.

This study describes the characterization of seven H5N1 avian influenza viruses from domestic ducks in Eastern China in 2011. Phylogenetic analysis showed these viruses were closely related to an H5N1 virus circulating in wild birds in Hong Kong. Some characteristics of these viruses were similar to those of an H5N1 strain that circulated in China and Vietnam (2003-2004). The virulence of three isolates was examined in chickens and mice, and they were found to be highly pathogenic in chickens but showed low pathogenicity in mice. These results suggest that continued H5N1 surveillance in poultry should be used as an early warning system for avian influenza outbreaks.

Biting activity and host attractancy of mosquitoes (Diptera: Culicidae) in Manzhouli, China.

The biting activity and host attractancy of vector mosquitoes are important in assessing the risk of arbovirus transmission, especially where migratory and nonmigrating bird species congregate, such as in Hulun Lake, Manzhouli. In 2009, the population distribution, species diversity, biting activity, and host attractancy of mosquitoes were investigated in Hulan Lake and its associated prairie area. The adult mosquitoes were captured either by human volunteers using aspirators in mosquito nets, by CO2-baited light traps, or by animal-baited traps. In total, 27,004 mosquitoes, representing three genera and 10 species, were collected from Manzhouli, China, in July 2009, of which Aedes dorsalis (Meigen) were most predominant species, followed by Ae. vexans (Meigen). Biting activity peaks by Ae.flavescens (Muller), Ae. dorsalis, and Culex modestus (Facalbi) on human subjects were investigated. Four mosquito species were captured from different animal sheds (sheep, cattle, and goose). Ae. flavescens was more abundant in the cattle shed than in the other two sheds. The Ae. dorsalis in the sheep shed was much higher than in the other animal sheds. The Ae.flavescens collected via chicken-baited traps were significantly higher than those collected via rabbit-baited and pigeon-baited traps. There were no significant differences in the number of Ae. dorsalis and Ae. vexans collected using the three different animal traps.

Overproduction of a potential red pigment by a specific self-immobilization biomembrane-surface liquid culture of Penicillium novae-zeelandiae.

A specific self-immobilization biomembrane-surface liquid culture (SIBSLC) was developed to overproduce a potential penicillium red pigment. Statistic analysis shows that both glucose concentration and membrane diameter are important factors influencing the yield of red pigment. After the optimization using central composite experimental design, the maximum yield of red pigment in shake flask reaches 4.25 g/l. The growth of strain HSD07B consists of three phases, and the pigment secreted in the decelerated phase, is originated from the interior of biomembrane where glucose exhaustion occurs. In addition, the batch and continuous SIBSLC were conducted for production of the pigment, and the latter was more competitive in consideration of the fact that it not only increased 61.5 % of pigment productivity, but also simplified the production process. Moreover, the pigment produced by SIBSLC is potentially acceptable for food applications although it is distinguished from the co-cultured red pigment we reported previously in components.

Granulomatous orchitis: case report and review of the literature.

We report the disease characteristics, diagnosis, and treatment of granulomatous orchitis. A 38-year-old man presented with a history of intermittent swelling, pain, and discomfort in the right testicle of 3 days' duration. Unenhanced magnetic resonance imaging (MRI) of the testis and scrotum revealed an oval mass in the right testis measuring approximately 17 mm in diameter, with clear borders and a target ring-like appearance from periphery to center. T1-weighted imaging (T1WI) showed uniform low-intensity signals, and T2WI showed mixed high- and low-intensity signals. Diffusion-weighted imaging (DWI) signals were iso-intense, and the outer ring on enhanced scans showed progressive enhancement. We performed radical resection of the right testis under combined spinal-epidural anesthesia. The pathological diagnosis was granulomatous right orchitis. Two months postoperatively, ultrasonography showed no testis and epididymal echo signals in the right scrotum, and no obvious abnormalities; color Doppler blood flow imaging (CDFI) findings were normal. Granulomatous orchitis is rare in clinical practice, and the cause is unknown. The disease involves non-specific inflammation; however, it is currently believed that antibiotics and steroids are ineffective for conservative treatment, and orchiectomy should be actively performed.

Multimodal cues facilitate ripe-fruit localization and extraction in free-ranging pteropodid bats.

Sensory cues play an important role in any plant-animal interaction. Yet, we know very little about the cues used by wild mammals during fruit selection. Existing evidence mainly comes from captive studies and suggests that the pteropodid bats rely on olfaction to find fruits. In this study, we avoided captivity-generated stressors and provide insights from natural selective forces by performing manipulative experiments on free-ranging fruit bats (Cynopterus sphinx) in a wild setting, in a tree species that exhibits a bat-fruit syndrome (Madhuca longifolia var. latifolia). We find that visual cues are necessary and sufficient to locate ripe fruits. Fruit experiments exhibiting visual cues alone received more bat visits than those exhibiting other combinations of visual and olfactory cues. Ripe fruit extractions were higher by bats that evaluated fruits by perching than hovering, indicating an additional cue, i.e., haptic cue. Visual cues appear to be informative over short distances, whereas olfactory and haptic cues facilitate the fruit evaluation for those bats that used hovering and perching strategies, respectively. This study also shows that adult bats were more skillful in extracting ripe fruits than the young bats, and there was a positive correlation between the weight of selected fruits and bat weight. This study suggests that the integration of multimodal cues (visual, olfactory and haptic) facilitate ripe-fruit localization and extraction in free-ranging pteropodid bats.

A Preliminary Study of Personalized Head CT Scan in Pediatric Patients.

OBJECTIVES: In the present study, we introduced a practical approach to quantify organ-specific radiation doses and investigated whether low-dose head circumference (HC)-based protocols for non-enhanced head computed tomography (CT) could reduce organs-specific radiation dose in pediatric patients while maintaining high image quality. METHODS: A total of 83 pediatric patients were prospectively recruited. Without limits to the HC, 15 patients were selected as a convention group (CON group) and underwent non-enhanced head CT scan with standard-dose protocols (tube current-time products of 250mAs). Low-dose group (LD group), including remaining 68 pediatrics were divided into 3 subgroups based on the HC: 54.1-57.0 cm for LD200mAs group (HC-based protocols of 200mAs), 51.1-54.0 cm for LD150mAs group (HC-based protocols of 150mAs), 48.1-51.0 cm for LD100mAs group (HC-based protocols of 100mAs). Subjective and objective image quality was evaluated and measured by 2 experienced radiologists. Radimetrics was used to calculate organs-specific radiation dose, including the brain, eye lenses, and salivary glands. RESULTS: In CON250mAs group, radiation doses in the brain and salivary glands were conversely correlated with HC, and pediatric patients with smaller HC received higher organs-specific radiation dose. Reducing tube current-time product from 250 to 100mAs could significantly reduce the organ-specific radiation dose. The subjective image quality score ≥ 3.0 is acceptable for diagnosis purposes. The signal to noise ratio (SNR) and the contrast to noise ratio (CNR) of bilateral thalamus and centrum semiovale in 3 LD subgroups were not statistically different compared with the CON group. CONCLUSION: Our research indicated that low-dose HC-based protocols of non-enhanced head CT scan can evidently reduce the organ-specific radiation doses, while maintaining high image quality. HC can serve as a vital tool to guide personalized low-dose head CT scan for pediatric patients.

Correction to Ultrasonic-Assisted Ionic Liquid Extraction of Two Biflavonoids from Selaginella tamariscina.

[This corrects the article DOI: 10.1021/acsomega.0c04723.].

A biomimetic fish finlet with a liquid metal soft sensor for proprioception and underwater sensing.

Finlets have a unique overhanging structure at the back, similar to a flag. They are located between the dorsal/anal fin and the caudal fin on the sides of the body. Until now, the sensing ability of finlets has not been well understood. In this paper, we design and manufacture a biomimetic soft robotic finlet (48.5 mm long, 30 mm high) with mechanosensation based on printed stretchable liquid metal sensors. The robotic finlet's posterior fin ray can achieve side-to-side movement orthogonal to the anterior fin ray. A flow sensor encapsulating a liquid metal sensor network enables the biomimetic finlets to sense the direction and flow intensity. The stretchable liquid metal sensors mounted on micro-actuators are utilized to perceive the swing motion of the fin ray. We found that the finlet prototype can sense the flapping amplitudes and frequency of the fin ray. The membrane between the two orthogonal fin rays can amplify the sensor output. Our results indicate that the overhanging structure endows the biomimetic finlet with the ability to sense external stimuli from stream-wise, lateral and vertical directions. We further demonstrate, through digital particle image velocimetry experiments, that the finlet can detect a Kármán vortex street. This study lays the foundations for exploring the environmental perception of biological fish fins and provides a new approach for the perception of complex flow environments by future underwater robots.

Homogenate-Ultrasound-Assisted Ionic Liquid Extraction of Total Flavonoids from Selaginella involven: Process Optimization, Composition Identification, and Antioxidant Activity.

In this paper, an efficient approach to extract total flavonoids (TFs) from Selaginella involvens (Sw.) Spring using homogenate-ultrasound-assisted ionic liquid (IL) extraction (HUA-ILE) was first developed. The results indicated that EPyBF4 was selected as the suitable extractant. According to the single factor experiment and response surface methodology, the IL concentration of 0.10 mol/L, the extraction time of 160 s, the liquid/solid ratio of 13:1 mL/g, and the extraction power of 300 W were concluded as the best conditions. A yield of 8.48 ± 0.27 mg/g TF content was obtained. Compared with HUA ethanol extraction, ultrasound-assisted IL extraction, and percolation extraction, the TF content obtained by the HUA-ILE method could be increased by 2 to 4 times, and the extraction time could be reduced by 100 times. Furthermore, 16 compounds of the TF extract were finally identified through ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry, among which 11 compounds were first discovered in S. involven. The contents of six biflavonoids in S. involven were determined simultaneously adopting high-performance liquid chromatography, including amentoflavone, hinokiflavone, bilobetin, ginkgetin, isoginkgetin, and heveaflavone. The TF extract in S. involven was proved to have potent antioxidant activity through the four antioxidant experiments. In conclusion, HUA-ILE was applied for the first time to exploit a green, efficient, and novel approach to extract TFs, and the research also provided promising prospects for applications of S. involven.