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Background: When companies are uncertain about the potential of a new formulation to be bioequivalent to a Reference product, it is common practice to carry out downsized pilot studies as a gatekeeping in vivo strategy to decide whether to move forward or not with a full-size pivotal study. However, due to the small study size, these studies are inarguably more sensitive to variability. Objectives: To address and mitigate the uncertainty of the conclusions of pilot studies concerning the maximum observed concentration (C[sub.max]), the f [sub.2] factor was proposed as an alternative approach to the average bioequivalence statistical methodology. Methods: In this work, the alternative methodology is applied to pharmacokinetic data from pilot bioequivalence trials performed with pazopanib 200 mg and 400 mg. Results: Despite the small sample size, and very high intra-subject variability, the f [sub.2] factor demonstrated the potential for predicting bioequivalence. The positive results were confirmed in the full sized pivotal studies. Conclusions: In conclusion, this alternate methodology shows promise in reducing uncertainty associated with pilot studies and aiding in decisions to go forward with pivotal bioequivalence studies.

Primary cardiac tumours are relatively uncommon (75% are benign). Across the other 25%, representing malignant neoplasia, sarcomas account for 75–95%, and primary cardiac intimal sarcoma (PCIS) is one of the rarest findings. We aimed to present a comprehensive review and practical considerations from a multidisciplinary perspective with regard to the most recent published data in the specific domain of PCIS. We covered the issues of awareness amid daily practice clinical presentation to ultra-qualified management in order to achieve an adequate diagnosis and prompt intervention, also emphasizing the core role of MDM2 immunostaining and MDM2 genetic analysis. An additional base for practical points was provided by a novel on-point clinical vignette with MDM2-positive status. According to our methods (PubMed database search of full-length, English publications from January 2021 to March 2023), we identified three studies and 23 single case reports represented by 22 adults (male-to-female ratio of 1.2; male population with an average age of 53.75 years, range: 35–81; woman mean age of 55.5 years, range: 34–70) and a 4-year-old child. The tumour-related clinical picture was recognized in a matter of one day to ten months on first admission. These non-specific data (with a very low index of suspicion) included heart failure at least NYHA class II, mitral regurgitation and pulmonary hypertension, acute myocardial infarction, ischemic stroke, obstructive shock, and paroxysmal atrial fibrillation. Awareness might come from other complaints such as (most common) dyspnoea, palpitation, chest pressure, cough, asthenia, sudden fatigue, weakness, malaise, anorexia, weight loss, headache, hyperhidrosis, night sweats, and epigastric pain. Two individuals were initially misdiagnosed as having endocarditis. A history of prior treated non-cardiac malignancy was registered in 3/23 subjects. Distant metastasis as the first step of detection (n = 2/23; specifically, brain and intestinal) or during follow-up (n = 6/23; namely, intestinal, brain and bone, in two cases for each, and adrenal) required additional imagery tools (26% of the patients had distant metastasis). Transoesophageal echocardiography, computed tomography (CT), magnetic resonance imagery, and even [sup.18]F-FDG positronic emission tomography-CT (which shows hypermetabolic lesions in PCIS) represent the basis of multimodal tools of investigation. Tumour size varied from 3 cm to ≥9 cm (average largest diameter of 5.5 cm). The most frequent sites were the left atrium followed by the right ventricle and the right atrium. Post-operatory histological confirmation was provided in 20/23 cases and, upon tumour biopsy, in 3/23 of them. The post-surgery maximum free-disease interval was 8 years, the fatal outcome was at the earliest two weeks since initial admission. MDM2 analysis was provided in 7/23 subjects in terms of MDM2-positive status (two out of three subjects) at immunohistochemistry and MDM2 amplification (four out of five subjects) at genetic analysis. Additionally, another three studies addressed PCISs, and two of them offered specific MDM2/MDM2 assays (n = 35 patients with PCISs); among the provided data, we mention that one cohort (n = 20) identified a rate of 55% with regard to MDM2 amplification in intimal sarcomas, and this correlated with a myxoid pattern; another cohort (n = 15) showed that MDM2-positive had a better prognostic than MDM2-negative immunostaining. To summarize, MDM2 amplification and co-amplification, for example, with MDM4, CDK4, HMGA3, CCND3, PDGFRA, TERT, KIT, CCND3, and HDAC9, might improve the diagnosis of PCIS in addition to MDM2 immunostaining since 10–20% of these tumours are MDM2-negative. Further studies are necessary to highlight MDM2 applicability as a prognostic factor and as an element to be taken into account amid multi-layered management in an otherwise very aggressive malignancy.

A series of indazole derivatives were designed and synthesized by molecular hybridization strategy, and these compounds were evaluated the inhibitory activities against human cancer cell lines of lung (A549), chronic myeloid leukemia (K562), prostate (PC-3), and hepatoma (Hep-G2) by methyl thiazolyl tetrazolium (MTT) colorimetric assay. Among these, compound 6o exhibited a promising inhibitory effect against the K562 cell line with the IC[sub.50] (50% inhibition concentration) value of 5.15 µM, and this compound showed great selectivity for normal cell (HEK-293, IC[sub.50] = 33.2 µM). Moreover, compound 6o was confirmed to affect apoptosis and cell cycle possibly by inhibiting Bcl2 family members and the p53/MDM2 pathway in a concentration-dependent manner. Overall, this study indicates that compound 6o could be a promising scaffold to develop an effective and low-toxic anticancer agent.

A novel electrochemiluminescence (ECL) method was developed for determination of protein kinase A (PKA) ultra-sensitively based on amidated nano-titanium (NH.sub.2-TiO.sub.2) embellished carbon dots (Mg@N-CDs) fluorescent probe, which integrated the target recognition and ECL signal enhancement. The Cys-labeled kemptides were employed to build a serine-rich synthetic substrate-heptapeptide (Cys-kemptide) on the Au-electrode surface. Then, the PKA-induced biosensor was triggered as a signal switch to introduce the large amounts of TiO.sub.2 decorated Mg@N-CD nanohybrid (Ti@NMg-CDs) into AuE/Cys-phosphopeptides for signal output. In particular, the presence of PKA could induce the formation of Cys-phosphopeptides by the catalytic reaction between specific substrate (kemptide) and PKA, which acts as an initiator to link the Ti@NMg-CDs according to the bridge interactions Ti-O-P. In this way, multiple Cys-phosphopeptides were adsorbed onto a single Ti@NMg-CDs, and the Ti@NMg-CDs not only provided high specific selectivity but also large surface area, as well as unprecedented high ECL efficiency. Using this PKA-induced enhanced sensor, the limit of detection of the PKA was 4.89 x 10.sup.-4 U/mL (S/N = 3). The proposed ECL biosensor was also universally applicable for the screening of PKA inhibitors and determining of other kinases activity. Our sensing system has excellent performance of specificity and the screening of kinase inhibitors, as well as it will inspire future effort in clinical diagnostics and new drug discovery. Graphical

This study aimed to develop a supersaturated liquid formulation (SSLF) to enhance the solubility and dissolution of pazopanib hydrochloride (PZH). SSLFs were prepared by a simple stirring method in a heated silicon oil bath (70 °C). PZH showed highly pH-dependent solubility (pH 1.2 > water >> pH 4.0 and pH 6.8) at 37 °C. The SSLF containing glycerol and polyvinylpyrrolidone K30 (PVP K30) increased PZH dispersion solubility (273.66 ± 48.91 μg/mL) at pH 6.8 by more than 50-fold compared with that of glycerol alone (<5 μg/mL), and the PZH precipitate particle size was considerably small (<100 nm). Moreover, the dispersion solubility of PZH from SSLF containing additional propylene glycol (PG) increased to 364.41 ± 2.47 μg/mL. The optimized SSLF10 (PZH/glycerol/PG/PVP K30 = 10/50/20/20, w/w) exhibited a high dissolution rate at pH 4.0 (>90%) and 6.8 (>55%) until 360 min, whereas PZH powder and PZH glycerol solution showed pH-dependent, low dissolution rates (<10%) under similar conditions. The supersaturation ratio of SSLF10 was very high at 29.88 and 18.36 at pH 6.8 and 4.0, respectively, indicating a stable PZH supersaturation solution. In the transmission electron microscopy analysis, PVP K30 and PG in SSLF10 synergistically suppressed PZH precipitation and recrystallization with small amorphous particles (<200 nm). Therefore, SSLF10 would be a promising formulation with enhanced solubility and dissolution rates regardless of medium pH.

Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer.This Opinion discusses three different mechanisms by which high-dose vitamin C can be selectively toxic to cancer cells. These findings from preclinical studies will be beneficial for the design of clinical trials testing high-dose vitamin C as an anticancer therapy.

In a randomized trial involving previously untreated patients with metastatic intermediate- or poor-risk renal-cell cancer, nivolumab plus ipilimumab was associated with higher response rates, longer overall survival, and greater improvement in quality of life than sunitinib.

Angiogenesis is the formation of new blood vessels from pre-existing vessels. It is a highly regulated process as determined by the interplay between pro-angiogenic and anti-angiogenic factors. Under certain conditions the balance between angiogenesis stimulators and inhibitors is altered, which results in a shift from physiological to pathological angiogenesis. Therefore, the goal of therapeutic targeting of angiogenic process is to normalize vasculature in target tissues by enhancing angiogenesis in disease conditions of reduced vascularity and blood flow, such as tissue ischemia, or alternatively to inhibit excessive and abnormal angiogenesis in disorders like cancer. Gold nanoparticles (AuNPs) are special particles that are generated by nanotechnology and composed of an inorganic core containing gold which is encircled by an organic monolayer. The ability of AuNPs to alter vasculature has captured recent attention in medical literature as potential therapeutic agents for the management of pathologic angiogenesis. This review provides an overview of the effects of AuNPs on angiogenesis and the molecular mechanisms and biomedical applications associated with their effects. In addition, the main synthesis methods, physical properties, uptake mechanisms, and toxicity of AuNPs are briefly summarized. Keywords: gold nanoparticles, angiogenesis, molecular signaling, VEGF, uptake, toxicity

Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3′ partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3′ partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.