Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Background: Oliceridine is a novel G protein-biased ligand µ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).

Active DNA Demethylase, TET1, Increases Oxidative Phosphorylation and Sensitizes Ovarian Cancer Stem Cells to Mitochondrial Complex I Inhibitor.

Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.

High-Affinity Superantigen-Based Trifunctional Immune Cell Engager Synergizes NK and T Cell Activation for Tumor Suppression.

The development of immune cell engagers (ICEs) can be limited by logistical and functional restrictions associated with fusion protein designs, thus limiting immune cell recruitment to solid tumors. Herein, a high affinity superantigen-based multivalent ICE is developed for simultaneous activation and recruitment of NK and T cells for tumor treatment. Yeast library-based directed evolution is adopted to identify superantigen variants possessing enhanced binding affinity to immunoreceptors expressed on human T cells and NK cells. High-affinity superantigens exhibiting improved immune-stimulatory activities are then incorporated into a superantigen-based tri-functional yeast-display-enhanced multivalent immune cell engager (STYMIE), which is functionalized with a nanobody, a Neo-2/15 cytokine, and an Fc domain for tumor targeting, immune stimulation, and prolonged circulation, respectively. Intravenous administration of STYMIE enhances NK and T cell recruitment into solid tumors, leading to enhanced inhibition in multiple tumor models. The study offers design principles for multifunctional ICEs.

Overcoming the nutritional immunity by engineering iron-scavenging bacteria for cancer therapy.

Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome of E. coli colonized in murine tumors. Compared to E. coli cultivated in the rich medium, we found that E. coli colonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment to E. coli. We also found that the colonization of E. coli in the tumor led to an increased expression of lipocalin 2 (LCN2), a host protein that can sequester the enterobactin. We therefore engineered E. coli in order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, the E. coli synthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. coli showed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. coli treatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria's ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.

[Analysis and prospect of correlation between relative molecular weight and efficacy of polysaccharides from medicinal plant resources].

Polysaccharides from medicinal plant resources are a kind of polymers extracted from medicinal plants. They are complex long chains formed by different monosaccharides connected via glucosidic bonds. These polysaccharides usually have straight chain and branched chain structures, and their relative molecular weight changes greatly. Modern studies have shown that the biological activi-ty of polysaccharides from medicinal plant resources is closely related to their relative molecular weight. This paper first reviewed the preparation and detection methods of polysaccharides from medicinal plant resources with different relative molecular weights. Then, the paper summarized and analyzed the general experience of the correlation between efficacy and relative molecular weight of polysaccharides from medicinal plant resources with different molecular weights. It was considered that polysaccharides with large relative molecular weights(>100 kDa) play a leading role in immune regulation. Polysaccharides with medium relative molecular weights(10-100 kDa) play a leading role in immune regulation and the protection of the liver. Polysaccharides with small relative molecular weights(<10 kDa) play a leading role in anti-oxidation, regulation of intestinal flora, regulation of blood glucose and lipids, anti-fatigue, and the protection of nerves. Therefore, precise development of polysaccharides from medicinal plant resources based on relative molecular weight is expected to improve their biological activity and application value.

PBX1 as a novel master regulator in cancer: Its regulation, molecular biology, and therapeutic applications.

PBX1 is a critical transcription factor at the top of various cell fate-determining pathways. In cancer, PBX1 stands at the crossroads of multiple oncogenic signaling pathways and mediates responses by recruiting a broad repertoire of downstream targets. Research thus far has corroborated the involvement of PBX1 in cancer proliferation, resisting apoptosis, tumor-associated neoangiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, immune evasion, genome instability, and dysregulating cellular metabolism. Recently, our understanding of the functional regulation of the PBX1 protein has advanced, as increasing evidence has depicted a regulatory network consisting of transcriptional, post-transcriptional, and post-translational levels of control mechanisms. Furthermore, accumulating studies have supported the clinical utilization of PBX1 as a prognostic or therapeutic target in cancer. Preliminary results showed that PBX1 entails vast potential as a targetable master regulator in the treatment of cancer, particularly in those with high-risk features and resistance to other therapeutic strategies. In this review, we will explore the regulation, protein-protein interactions, molecular pathways, clinical application, and future challenges of PBX1.

Properties of [18F]FAPI monitoring of acute radiation pneumonia versus [18F]FDG in mouse models.

OBJECTIVE: In this study, the uptake characteristics of [18F]fibroblast activation protein inhibitor (FAPI) molecular imaging probe were investigated in acute radiation pneumonia and lung cancer xenografted mice before and after radiation to assess the future applicability of [18F]FAPI positron emission tomography/computed tomography (PET/CT) imaging in early radiotherapy response. METHODS: Initially, the biodistribution of [18F]FAPI tracer in vivo were studied in healthy mice at each time-point. A comparison of [18F]FAPI and [18F]fluorodeoxyglucose (FDG) PET/CT imaging efficacy in normal ICR, LLC tumor-bearing mice was evaluated. A radiation pneumonia model was then investigated using a gamma counter, small animal PET/CT, and autoradiography. The uptake properties of [18F]FAPI in lung cancer and acute radiation pneumonia were investigated using autoradiography and PET/CT imaging in mice. RESULTS: The tumor area was visible in [18F]FAPI imaging and the tracer was swiftly eliminated from normal tissues and organs. There was a significant increase of [18F]FDG absorption in lung tissue after radiotherapy compared to before radiotherapy, but no significant difference of [18F]FAPI uptake under the same condition. Furthermore, both the LLC tumor volume and the expression of FAP-ɑ decreased after thorax irradiation. Correspondingly, there was no notable [18F]FAPI uptake after irradiation, but there was an increase of [18F]FDG uptake in malignancies and lungs. CONCLUSIONS: The background uptake of [18F]FAPI is negligible. Moreover, the uptake of [18F]FAPI may not be affected by acute radiation pneumonitis compared to [18F]FDG, which may be used to more accurately evaluate early radiotherapy response of lung cancer with acute radiation pneumonia.

Specific molecular weight of Lycium barbarum polysaccharide for robust breast cancer regression by repolarizing tumor-associated macrophages.

The pro-tumorigenic M2-type tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment (TME) promote the progression, angiogenesis, and metastasis of breast cancer. The repolarization of TAMs from an M2-type toward an M1-type holds great potential for the inhibition of breast cancer. Here, we report that Lycium barbarum polysaccharides (LBPs) can significantly reconstruct the TME by modulating the function of TAMs. Specifically, we separated four distinct molecular weight segments of LBPs and compared their repolarization effects on TAMs in TME. The results showed that LBP segments within 50-100 kDa molecular weight range exhibited the prime effect on the macrophage repolarization, augmented phagocytosis effect of the repolarized macrophages on breast cancer cells, and regression of breast tumor in a tumor-bearing mouse model. In addition, RNA-sequencing confirms that this segment of LBP displays an enhanced anti-breast cancer effect through innate immune responses. This study highlights the therapeutic potential of LBP segments within the 50-100 kDa molecular weight range for macrophage repolarization, paving ways to offer new strategies for the treatment of breast cancer.

Research on heart rate extraction method based on mobile phone video.

As an important indicator of human health, heart rate is related to the diagnosis of cardiovascular diseases. In recent years, extracting the heart rate from the mobile phone image has become a research hotspot. However, the illumination intensity of the background, frame rate of the video, and resolution of the image influence heart rate detection accuracy. To overcome these problems, this study proposed a novel heart rate extraction method based on mobile video. Firstly, the mobile phone camera is engaged to record the finger video, the region of interest (ROI) is extracted through the iterative threshold, and the pulse signal is obtained according to the grayscale change of the resolution within the ROI. Then, a low-pass and a high-pass Butterworth filters are exploited to filter out the noise and interframes from the extracted pulse signal. Finally, an improved adaptive peak extraction algorithm is proposed to detect the pulse peaks and the heart rate derived from the difference in pulse peaks. The experimental results show that light intensity, frame rate and resolution all have an influence on the heart rate extraction accuracy, with the most obvious influence of light, the average accuracy of the experiment can reach 99.32 % under good lighting conditions, while only 72.23 % under poor lighting conditions. In terms of frame rate, increasing the frame rate from 30 fps to 60 fps, the accuracy is improved by 0.9 %. For the resolution, increasing the resolution from 1080 p to 2160 p, the accuracy is improved by 1.12 %. While comparing the proposed method with existing methods, the proposed method has a higher accuracy rate, which has important practical value and application prospects in telemedicine and daily monitoring.

Pharmacokinetics, safety, and efficacy of GM1 ganglioside in healthy subjects and patients with multiple myeloma: Two dose-escalation studies.

PURPOSE: This study aimed to assess the pharmacokinetics, safety, and efficacy of GM1 in healthy Chinese subjects and patients with multiple myeloma. METHODS: The data used in this study was derived from two dose-escalation trials: GM1-101, involving 70 healthy subjects, and GM1-201, which included 160 multiple myeloma patients. Population pharmacokinetics (PopPK) analysis was conducted on a subset of 90 participants using a nonlinear mixed-effects approach, and potential covariates were explored quantitatively. Observations of any abnormalities in vital signs, physical examinations, laboratory tests, and electrocardiograms during the study period, along with any spontaneously reported and directly observed adverse events, were documented for safety evaluation. Furthermore, neurotoxicity scales were used to assess the efficacy of GM1 as a prophylaxis for chemotherapy-induced peripheral neuropathy and to perform exposure-response analyses in conjunction with pharmacokinetic parameters. RESULTS: A one-compartment model with first-order elimination best characterized the pharmacokinetics of GM1. The clearance and volume of distribution, as estimated by the final model, were 0.0942 L/h and 3.27 L for GM1-A, and 0.0714 L/h and 2.82 L for GM1-B, respectively. Covariates such as sex, body weight, and albumin significantly influenced pharmacokinetic parameters, yet the variation in steady-state exposure between subjects and reference subjects was less than 45% within their 90% confidence interval. Adverse reactions related to GM1 occurred in 20 (28.6%) and 57 (35.6%) subjects in the GM1-101 and GM1-201 cohorts, respectively. The changes in TNSc and FACT-Ntx scores from baseline at the end of periods 4 and 6 were lower in each GM1 dose group compared to the blank control group. The 400 mg dose group of GM1 displayed greater effectiveness than other dose groups. However, exposure-response analysis revealed no significant modification in efficacy with increasing GM1 exposure. CONCLUSIONS: This study provides the first population pharmacokinetic analysis of GM1. GM1 exhibits a favorable safety profile among healthy subjects and patients with multiple myeloma. GM1 proved effective in mitigating chemotherapy-induced peripheral neuropathy, but this study observed no significant correlation between its efficacy and exposure. TRIAL REGISTRATION NUMBERS: ChiCTR2000041283 and ChiCTR2000041283.

Glucose Transporter 1-Mediated Transcytosis of Glucosamine-Labeled Liposomal Ceramide Targets Hypoxia Niches and Cancer Stem Cells to Enhance Therapeutic Efficacy.

Tumour hypoxia plays an important role in modulating tumorigenesis, angiogenesis, invasion, immunosuppression, resistance to treatment, and even maintenance of the stemness of cancer stem cells (CSCs). Moreover, the targeting and treatment of hypoxic cancer cells and CSCs to reduce the influence of tumor hypoxia on cancer therapy remains an imperative clinical problem that needs to be addressed. Since cancer cells upregulate the expression of glucose transporter 1 (GLUT1) through the Warburg effect, we considered the possibility of GLUT1-mediated transcytosis in cancer cells and developed a tumor hypoxia-targeting nanomedicine. Our experimental results indicate that glucosamine-labeled liposomal ceramide can be efficiently transported between cancer cells by GLUT1 transporters and substantially accumulated in the hypoxic area in in vitro CSC spheroids and in vivo tumor xenografts. We also verified the effects of exogenous ceramide on tumor hypoxia, including important bioactivities such as upregulation of p53 and retinoblastoma protein (RB), downregulation of hypoxia-inducible factor-1 alpha (HIF-1α) expression, disruption of the OCT4-SOX2 network of stemness, and inhibition of CD47 and PD-L1 expression. To achieve an ideal therapeutic outcome, we combined treatment of glucosamine-labeled liposomal ceramide with paclitaxel and carboplatin, and we found an excellent synergistic effect, with tumor clearance being noted in three-fourths of the mice. Overall, our findings provide a potential therapeutic strategy for the treatment of cancer.

Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

Synthesis and Preclinical Evaluation of 2-(4-[18F]Fluorophenyl)imidazo[1,2-h][1,7]naphthyridine ([18F]FPND-4): An Aza-Fused Tricyclic Derivative as Positron Emission Tomography Tracer for Neurofibrillary Tangle Imaging.

Tau accumulation is one of the predominant neuropathological biomarkers for in vivo diagnosis of Alzheimer's disease due to its high correlation with disease progression. In this study, we focused on the structure-activity relationship study of the substituent effect on the aza-fused tricyclic core imidazo[1,2-h][1,7]naphthyridine to screen 18F-labeled Tau tracers. Through a series of autoradiographic studies and biological evaluations, 4-[18F]fluorophenyl-substituted tracer [18F]13 ([18F]FPND-4) was identified as a promising candidate with high affinity to native Tau tangles (IC50 = 2.80 nM), few appreciable binding to Aß plaques and MAO-A/B. Validated by dynamic positron emission tomography (PET) imaging in rodents and rhesus monkey, [18F]13 displayed desirable brain uptake (SUV = 1.75 at 2 min), fast clearance (brain2min/60min = 5.9), minimal defluorination, and few off-target binding, which met the requirements of a Tau-specific PET radiotracer.

Frontier Review of the Molecular Mechanisms and Current Approaches of Stem Cell-Derived Exosomes.

Exosomes are effective therapeutic vehicles that may transport their substances across cells. They are shown to possess the capacity to affect cell proliferation, migration, anti-apoptosis, anti-scarring, and angiogenesis, via the action of transporting molecular components. Possessing immense potential in regenerative medicine, exosomes, especially stem cell-derived exosomes, have the advantages of low immunogenicity, minimal invasiveness, and broad clinical applicability. Exosome biodistribution and pharmacokinetics may be altered, in response to recent advancements in technology, for the purpose of treating particular illnesses. Yet, prior to clinical application, it is crucial to ascertain the ideal dose and any potential negative consequences of an exosome. This review focuses on the therapeutic potential of stem cell-derived exosomes and further illustrates the molecular mechanisms that underpin their potential in musculoskeletal regeneration, wound healing, female infertility, cardiac recovery, immunomodulation, neurological disease, and metabolic regulation. In addition, we provide a summary of the currently effective techniques for isolating exosomes, and describe the innovations in biomaterials that improve the efficacy of exosome-based treatments. Overall, this paper provides an updated overview of the biological factors found in stem cell-derived exosomes, as well as potential targets for future cell-free therapeutic applications.

Recent Advances in Metal-Based NanoEnhancers for Particle Therapy.

Radiotherapy is one of the most common therapeutic regimens for cancer treatment. Over the past decade, proton therapy (PT) has emerged as an advanced type of radiotherapy (RT) that uses proton beams instead of conventional photon RT. Both PT and carbon-ion beam therapy (CIBT) exhibit excellent therapeutic results because of the physical characteristics of the resulting Bragg peaks, which has been exploited for cancer treatment in medical centers worldwide. Although particle therapies show significant advantages to photon RT by minimizing the radiation damage to normal tissue after the tumors, they still cause damage to normal tissue before the tumor. Since the physical mechanisms are different from particle therapy and photon RT, efforts have been made to ameliorate these effects by combining nanomaterials and particle therapies to improve tumor targeting by concentrating the radiation effects. Metallic nanoparticles (MNPs) exhibit many unique properties, such as strong X-ray absorption cross-sections and catalytic activity, and they are considered nano-radioenhancers (NREs) for RT. In this review, we systematically summarize the putative mechanisms involved in NRE-induced radioenhancement in particle therapy and the experimental results in in vitro and in vivo models. We also discuss the potential of translating preclinical metal-based NP-enhanced particle therapy studies into clinical practice using examples of several metal-based NREs, such as SPION, Abraxane, AGuIX, and NBTXR3. Furthermore, the future challenges and development of NREs for PT are presented for clinical translation. Finally, we propose a roadmap to pursue future studies to strengthen the interplay of particle therapy and nanomedicine.

Impacts of embracing 39-week elective induction across an entire labor and delivery unit.

BACKGROUND: Induction of labor among low-risk, 39-week nulliparas increased significantly in the United States following publication of the outcomes of A Randomized Trial of Induction Versus Expectant Management trial. However, the rates of labor induction and outcomes in non-nulliparous patients and the wider impacts on the labor unit have not been reported widely. OBJECTIVE: This study aimed to compare the induction of labor rates and outcomes before and after liberal implementation of 39-week elective induction at a single center. STUDY DESIGN: This was a retrospective cohort study comparing the delivery characteristics of pregnancies 1 year before and 1 year after adoption of a new 39-week elective induction policy at a single, tertiary-care center. Notably, elective induction was not restricted to nulliparas. We examined all live, singleton, in-born deliveries ≥36 weeks gestation, excluding those with fetal anomalies and prolonged antenatal admission. Deliveries at ≥39 weeks gestation were further subcategorized as being high risk (diabetes mellitus, chronic hypertension, intrauterine growth restriction, history of fetal demise or cholestasis) or low risk, nulliparas vs multiparas, and with or without a previous cesarean delivery. Elective deliveries were those without a maternal, fetal, or obstetrical indication. Primary outcomes included gestational age and indications for delivery, rates of labor induction and elective induction, and time from admission to delivery. Secondary outcomes included the rate of cesarean deliveries, indications for cesarean deliveries, and maternal and newborn morbidities. The outcomes were compared using Wilcoxon rank-sum tests or chi-square tests as appropriate. The odds of cesarean delivery were analyzed using multivariate logistic regression and controlling for relevant confounders. RESULTS: A total of 2672 pre-implementation and 2526 post-implementation deliveries were studied. Among patients at ≥39 weeks gestation, elective delivery increased (pre-implementation, 344/1788 [19.2%] vs post-implementation, 684/1710 [40.0%]; P<.01) and admission for labor or ruptured membranes decreased (pre-implementation, 920/1788 [51.5%] vs post-implementation, 579/1710 [33.9%]; P<.01). Labor induction in the 39th week of gestation increased among low-risk and high-risk nulliparas, multiparas, and those with a previous cesarean delivery (P<.05 for each pairwise comparison), and the rate of 39-week elective inductions increased in all low-risk subgroups. Deliveries at 36 to 38 weeks gestation were similar in the proportion, timing, indications for delivery, and rate of labor induction. The odds of cesarean delivery was unchanged overall (adjusted odds ratio, 0.97; 95% confidence interval, 0.83-1.14) and for low-risk, ≥39-week nulliparas (adjusted odds ratio, 0.90; 95% confidence interval, 0.66-1.23) and low-risk, ≥39-week multiparas (adjusted odds ratio, 1.18; 95% confidence interval, 0.71-1.98). Among all deliveries, the median (interquartile range) time from admission to delivery increased significantly (pre-implementation, 12.8 [6.0-21.6] hours vs post-implementation, 15.6 [7.1-25.1] hours; P<.01) and the total cumulative patient care time from admission to delivery increased by 15% (pre-implementation, 41,578 hours vs post-implementation, 47,605 hours) when normalized by delivery volume. Chorioamnionitis incidence increased, whereas other maternal and neonatal morbidities were unchanged. CONCLUSION: Following adoption of a nonrestrictive, 39-week elective induction policy at a single, tertiary-care center, the rates of 39-week induction of labor and elective inductions increased among nulliparas, multiparas, and those with a previous cesarean delivery. The rate of cesarean delivery was unchanged, and the median time from admission to delivery and the cumulative admission to delivery hours increased significantly. Future studies are needed to further explore the full scope of the impacts on labor unit operations, costs, and patient experiences and outcomes.

Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.

Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.

Development of a TNF-α-mediated Trojan Horse for bacteria-based cancer therapy.

Tumor necrosis factor α (TNF-α) is upregulated in a chronic inflammatory environment, including tumors, and has been recognized as a pro-tumor factor in many cancers. Applying the traditional TNF-α antibodies that neutralize TNF-α activity, however, only exerts modest anti-tumor efficacy in clinical studies. Here, we develop an innovative approach to target TNF-α that is distinct from the neutralization mechanism. We employed phage display and yeast display to select non-neutralizing antibodies that can piggyback on TNF-α and co-internalize into cells through receptor ligation. When conjugating with toxins, the antibody exhibited cytotoxicity to cancer cells in a TNF-α-dependent manner. We further implemented the immunotoxin to an E. coli vehicle specially engineered for a high secretion level. In a syngeneic murine melanoma model, the bacteria stimulated TNF-α expression that synergized with the secreted immunotoxin and greatly inhibited tumor growth. The treatment also dramatically remodeled the tumor microenvironment in favor of several anti-tumor immune cells, including N1 neutrophils, M1 macrophages, and activated CD4+ and CD8+ lymphocytes. We anticipate that our new piggyback strategy is generalizable to targeting other soluble ligands and/or conjugates with different drugs for managing a diverse set of diseases.

A Few-Shot Learning Approach Assists in the Prognosis Prediction of Magnetic Resonance-Guided Focused Ultrasound for the Local Control of Bone Metastatic Lesions.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) constitutes a noninvasive treatment strategy to ablate deep-seated bone metastases. However, limited evidence suggests that, although cytokines are influenced by thermal necrosis, there is still no cytokine threshold for clinical responses. A prediction model to approximate the postablation immune status on the basis of circulating cytokine activation is thus needed. IL-6 and IP-10, which are proinflammatory cytokines, decreased significantly during the acute phase. Wound-healing cytokines such as VEGF and PDGF increased after ablation, but the increase was not statistically significant. In this phase, IL-6, IL-13, IP-10, and eotaxin expression levels diminished the ongoing inflammatory progression in the treated sites. These cytokine changes also correlated with the response rate of primary tumor control after acute periods. The few-shot learning algorithm was applied to test the correlation between cytokine levels and local control (p = 0.036). The best-fitted model included IL-6, IL-13, IP-10, and eotaxin as cytokine parameters from the few-shot selection, and had an accuracy of 85.2%, sensitivity of 88.6%, and AUC of 0.95. The acceptable usage of this model may help predict the acute-phase prognosis of a patient with painful bone metastasis who underwent local MRgFUS. The application of machine learning in bone metastasis is equivalent or better than the current logistic regression.