VERU-111, an Orally Available Tubulin Inhibitor, Suppresses Ovarian Tumor Growth and Metastasis.

Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, well-tolerated, and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and, ultimately, apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment for ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. Significance Statement VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo anti-tumor and anti-metastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.

USP12 facilitates gastric cancer progression via stabilizing YAP.

The dysregulation of Hippo signaling is a crucial factor driving the progression of gastric cancer, making the targeting of the Hippo pathway a promising therapeutic strategy. However, effective drugs targeting the Hippo/YAP axis remain unavailable. Thus, identifying potential therapeutic targets and mechanisms that inhibit the activity of the Hippo/YAP axis in gastric cancer is of paramount importance. The ubiquitination modification of the Hippo/YAP pathway plays a significant role in signaling transduction and cancer progression. In an effort to shed light on effective therapeutic targets, we conducted a screening using a deubiquitinase small interfering RNA library, leading to the identification of USP12 as an important deubiquitinase in the context of Hippo/YAP axis and the progression of gastric cancer. Our bioinformatic analysis further demonstrated a correlation between USP12 and poor survival, as well as a positive association with classical YAP target genes in gastric cancer samples. Notably, USP12 depletion was found to inhibit gastric cancer progression via the Hippo/YAP axis, whereas USP12 overexpression exhibited the opposite effect, promoting gastric cancer growth and enhancing YAP activity. Further studies through immuno-staining and immuno-precipitation assays indicated the nuclear localization of USP12 and its association with YAP to enhance YAP stability. Specifically, our findings revealed that USP12 could inhibit K48-linked poly-ubiquitination of YAP, predominantly at the K315 site. As a result, we have identified a novel regulatory mechanism involving USP12 and Hippo signaling in the progression of gastric cancer, with the potential for blockade of USP12 to materialize as a promising strategy for combating gastric cancer.

Need for Objective Task-Based Evaluation of Image Segmentation Algorithms for Quantitative PET: A Study with ACRIN 6668/RTOG 0235 Multicenter Clinical Trial Data.

Reliable performance of PET segmentation algorithms on clinically relevant tasks is required for their clinical translation. However, these algorithms are typically evaluated using figures of merit (FoMs) that are not explicitly designed to correlate with clinical task performance. Such FoMs include the Dice similarity coefficient (DSC), the Jaccard similarity coefficient (JSC), and the Hausdorff distance (HD). The objective of this study was to investigate whether evaluating PET segmentation algorithms using these task-agnostic FoMs yields interpretations consistent with evaluation on clinically relevant quantitative tasks. Methods: We conducted a retrospective study to assess the concordance in the evaluation of segmentation algorithms using the DSC, JSC, and HD and on the tasks of estimating the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of primary tumors from PET images of patients with non-small cell lung cancer. The PET images were collected from the American College of Radiology Imaging Network 6668/Radiation Therapy Oncology Group 0235 multicenter clinical trial data. The study was conducted in 2 contexts: (1) evaluating conventional segmentation algorithms, namely those based on thresholding (SUVmax40% and SUVmax50%), boundary detection (Snakes), and stochastic modeling (Markov random field-Gaussian mixture model); (2) evaluating the impact of network depth and loss function on the performance of a state-of-the-art U-net-based segmentation algorithm. Results: Evaluation of conventional segmentation algorithms based on the DSC, JSC, and HD showed that SUVmax40% significantly outperformed SUVmax50%. However, SUVmax40% yielded lower accuracy on the tasks of estimating MTV and TLG, with a 51% and 54% increase, respectively, in the ensemble normalized bias. Similarly, the Markov random field-Gaussian mixture model significantly outperformed Snakes on the basis of the task-agnostic FoMs but yielded a 24% increased bias in estimated MTV. For the U-net-based algorithm, our evaluation showed that although the network depth did not significantly alter the DSC, JSC, and HD values, a deeper network yielded substantially higher accuracy in the estimated MTV and TLG, with a decreased bias of 91% and 87%, respectively. Additionally, whereas there was no significant difference in the DSC, JSC, and HD values for different loss functions, up to a 73% and 58% difference in the bias of the estimated MTV and TLG, respectively, existed. Conclusion: Evaluation of PET segmentation algorithms using task-agnostic FoMs could yield findings discordant with evaluation on clinically relevant quantitative tasks. This study emphasizes the need for objective task-based evaluation of image segmentation algorithms for quantitative PET.

Efficacy and acceptability of adjunctive n-acetylcysteine for psychotic disorders: Systematic review and meta-analysis.

INTRODUCTION: N-acetylcysteine (NAC) augmentation of antipsychotic medication has been studied in psychotic disorders but the results are inconsistent. This meta-analysis aimed to evaluate the efficacy and acceptability of NAC as an augmentation strategy for psychotic disorders. METHODS: PubMed, Web of Science, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched until the date of November 28, 2022. The inclusion criteria were randomized controlled trials (RCTs) comparing NAC and placebo in patients with psychotic disorders. The outcomes were the psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and drop-out rates. RESULTS: A total of 594 patients from eight trials were included. The results showed that no difference was found in score changes of PANSS total, positive, negative, or general psychopathology scale scores between the NAC group and placebo group in both time points (≤24 weeks and >24 weeks). There was also no statistical difference in drop-out rates between the two groups. CONCLUSION: For the moment, it is not appropriate to recommend NAC as an augmentation of antipsychotic medication to treat psychotic disorders in routine clinical practice.

Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer.

BACKGROUND: The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed. METHODS: We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression. RESULTS: In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer. CONCLUSION: In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer.

Need for objective task-based evaluation of AI-based segmentation methods for quantitative PET.

Artificial intelligence (AI)-based methods are showing substantial promise in segmenting oncologic positron emission tomography (PET) images. For clinical translation of these methods, assessing their performance on clinically relevant tasks is important. However, these methods are typically evaluated using metrics that may not correlate with the task performance. One such widely used metric is the Dice score, a figure of merit that measures the spatial overlap between the estimated segmentation and a reference standard (e.g., manual segmentation). In this work, we investigated whether evaluating AI-based segmentation methods using Dice scores yields a similar interpretation as evaluation on the clinical tasks of quantifying metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of primary tumor from PET images of patients with non-small cell lung cancer. The investigation was conducted via a retrospective analysis with the ECOG-ACRIN 6668/RTOG 0235 multi-center clinical trial data. Specifically, we evaluated different structures of a commonly used AI-based segmentation method using both Dice scores and the accuracy in quantifying MTV/TLG. Our results show that evaluation using Dice scores can lead to findings that are inconsistent with evaluation using the task-based figure of merit. Thus, our study motivates the need for objective task-based evaluation of AI-based segmentation methods for quantitative PET.

Need for objective task-based evaluation of AI-based segmentation methods for quantitative PET.

Artificial intelligence (AI)-based methods are showing substantial promise in segmenting oncologic positron emission tomography (PET) images. For clinical translation of these methods, assessing their performance on clinically relevant tasks is important. However, these methods are typically evaluated using metrics that may not correlate with the task performance. One such widely used metric is the Dice score, a figure of merit that measures the spatial overlap between the estimated segmentation and a reference standard (e.g., manual segmentation). In this work, we investigated whether evaluating AI-based segmentation methods using Dice scores yields a similar interpretation as evaluation on the clinical tasks of quantifying metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of primary tumor from PET images of patients with non-small cell lung cancer. The investigation was conducted via a retrospective analysis with the ECOG-ACRIN 6668/RTOG 0235 multi-center clinical trial data. Specifically, we evaluated different structures of a commonly used AI-based segmentation method using both Dice scores and the accuracy in quantifying MTV/TLG. Our results show that evaluation using Dice scores can lead to findings that are inconsistent with evaluation using the task-based figure of merit. Thus, our study motivates the need for objective task-based evaluation of AI-based segmentation methods for quantitative PET.

Observer-study-based approaches to quantitatively evaluate the realism of synthetic medical images.

Objective.Synthetic images generated by simulation studies have a well-recognized role in developing and evaluating imaging systems and methods. However, for clinically relevant development and evaluation, the synthetic images must be clinically realistic and, ideally, have the same distribution as that of clinical images. Thus, mechanisms that can quantitatively evaluate this clinical realism and, ideally, the similarity in distributions of the real and synthetic images, are much needed.Approach.We investigated two observer-study-based approaches to quantitatively evaluate the clinical realism of synthetic images. In the first approach, we presented a theoretical formalism for the use of an ideal-observer study to quantitatively evaluate the similarity in distributions between the real and synthetic images. This theoretical formalism provides a direct relationship between the area under the receiver operating characteristic curve, AUC, for an ideal observer and the distributions of real and synthetic images. The second approach is based on the use of expert-human-observer studies to quantitatively evaluate the realism of synthetic images. In this approach, we developed a web-based software to conduct two-alternative forced-choice (2-AFC) experiments with expert human observers. The usability of this software was evaluated by conducting a system usability scale (SUS) survey with seven expert human readers and five observer-study designers. Further, we demonstrated the application of this software to evaluate a stochastic and physics-based image-synthesis technique for oncologic positron emission tomography (PET). In this evaluation, the 2-AFC study with our software was performed by six expert human readers, who were highly experienced in reading PET scans, with years of expertise ranging from 7 to 40 years (median: 12 years, average: 20.4 years).Main results.In the ideal-observer-study-based approach, we theoretically demonstrated that the AUC for an ideal observer can be expressed, to an excellent approximation, by the Bhattacharyya distance between the distributions of the real and synthetic images. This relationship shows that a decrease in the ideal-observer AUC indicates a decrease in the distance between the two image distributions. Moreover, a lower bound of ideal-observer AUC = 0.5 implies that the distributions of synthetic and real images exactly match. For the expert-human-observer-study-based approach, our software for performing the 2-AFC experiments is available athttps://apps.mir.wustl.edu/twoafc. Results from the SUS survey demonstrate that the web application is very user friendly and accessible. As a secondary finding, evaluation of a stochastic and physics-based PET image-synthesis technique using our software showed that expert human readers had limited ability to distinguish the real images from the synthetic images.Significance.This work addresses the important need for mechanisms to quantitatively evaluate the clinical realism of synthetic images. The mathematical treatment in this paper shows that quantifying the similarity in the distribution of real and synthetic images is theoretically possible by using an ideal-observer-study-based approach. Our developed software provides a platform for designing and performing 2-AFC experiments with human observers in a highly accessible, efficient, and secure manner. Additionally, our results on the evaluation of the stochastic and physics-based image-synthesis technique motivate the application of this technique to develop and evaluate a wide array of PET imaging methods.

Ubiquitous mitochondrial creatine kinase promotes the progression of gastric cancer through a JNK-MAPK/JUN/HK2 axis regulated glycolysis.

BACKGROUND: Ubiquitous mitochondrial creatine kinase (uMtCK) transfers high-energy phosphates from mitochondrially generated ATP to creatine to generate phosphocreatine. uMtCK overexpression has been reported in several malignant tumors, however, the clinical significance and impact of uMtCK in gastric cancer (GC) has not been comprehensively studied. METHODS: We first examined uMtCK expression in GC by quantitative real-time PCR and western blot assays. Then the clinicopathological significance of aberrant uMtCK expression was determined by immunohistochemical staining in a GC tissue microarray. Kaplan-Meier analysis was used for survival analysis. The biological functions of uMtCK in GC cells were explored by wound-healing, transwell assays and glucose metabolism assays in vitro as well as a liver metastasis model by spleen injection in nude mice in vivo. RESULTS: We verified that the expression of uMtCK was substantially elevated in GC tissues, significantly associating with a poorer prognosis in GC patients, especially for those with advanced stage. In univariate and multivariate analyses, uMtCK expression emerged as an independent prognostic factor for both disease-free survival and overall survival. Functionally, we demonstrated that uMtCK promoted glycolysis in GC cells and facilitated their migration, invasion and liver metastasis in vitro and in vivo. Mechanistically, uMtCK enhanced GC progression in a HK2-dependent glycolysis via acting the JNK-MAPK/JUN signaling pathway. CONCLUSIONS: uMtCK could serve as a novel independent prognostic biomarker as well as potential therapeutic target for GC patients, particularly for GC patients with an advanced UICC stage and tumor recurrence.

OTUB1 suppresses Hippo signaling via modulating YAP protein in gastric cancer.

Gastric cancer is one of the most lethal human malignancies in the world. Although great efforts are put in developing novel therapeutic targets, the effective targeting drugs are still limited. Recent studies reveal the abnormality of Hippo/YAP axis play critical role in the oncogenic process of gastric cancer. It is of great importance to demonstrate the regulation of Hippo signaling activity and YAP protein turnover in gastric cancer. Besides, the phosphorylation cascade on YAP function, which has been thoroughly investigated, the ubiquitination of YAP is also important in Hippo signaling status. Here, We utilized the DUB (Deubiquitinase) siRNA library to identify critical DUB for Hippo signaling. We discovered OTUB1 as a critical factor to facilitate gastric cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein. The clinical data analysis implicated OTUB1 was higher expressed in gastric cancer, which correlated with YAP activity and poor survival. OUTB1 interacted with YAP protein via its OTU domain (Ovarian tumor domain) and deubiquitinated YAP at several lysine sites (K90, K280, K343, K494 and K497), which subsequently inhibited YAP degradation. Our study revealed a novel deubiquitinase of Hippo/YAP axis and one possible therapeutic target for YAP-driven gastric cancer.

DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer.

BACKGROUND: The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why the YAP/TAZ proteins are activated in human cancers despite Hippo pathway activation. Recent studies have suggested that in addition to phosphorylation, several other posttranslational modifications, including ubiquitination, also play critical roles in modulating TAZ function. METHODS: We used several gastric cancer cell lines and performed western blot analysis, real-time PCR, immunoprecipitation assays, and in vitro ubiquitination assays and established a xenograft mouse model. RESULTS: Here, by screening a DUB (deubiquitinase) siRNA library, we discovered that DUB1 functions as a critical modulator that facilitates gastric cancer stemness and progression by deubiquitinating and activating the TAZ protein. We also found that DUB1 expression was elevated in gastric cancer and that elevated DUB1 expression correlated with TAZ activation and poor survival. DUB1 associates with the TAZ protein and deubiquitinates TAZ at several lysine residues, which subsequently stabilizes TAZ and facilitates its function. CONCLUSIONS: Our study revealed a novel deubiquitinase in the Hippo/TAZ axis and identified one possible therapeutic target for Hippo-driven gastric cancer.

UHRF1 modulates breast cancer cell growth via estrogen signaling.

The ubiquitination process, which involves that binding of an ubiquitin protein to certain substrates, regulates several human biological processes and human cancers. Several studies report that the abnormal expression of quite a few E3 ubiquitin ligases could play critical role in carcinogenic process and cancer progression. In our current study, we identify UHRF1 (Ubiquitin Like with PHD And Ring Finger Domain 1) is an important regulator for breast cancer growth. UHRF1 depletion significantly decreases breast cancer growth in vitro and in vivo. Clinical data analysis reveals that UHRF1 is dramatically elevated in breast cancer, compared to normal breast tissue. UHRF1 correlates with poor survival in luminal type of breast cancer patients, but not in ER-negative groups. The molecular biological studies show that UHRF1 localizes in the nuclear and interact with ERα via its SRA domain, which subsequently inhibits K48-linked ubiquitination of ERα and enhances ERα stability. Our study provides a novel function of UHRF1 in regulation estrogen signaling in breast cancer and a promising target for breast cancer therapeutics.

The shadow in the darkness: Case report on adhesive intestinal obstruction secondary to ventriculoperitoneal shunt catheter in an elderly patient.

Introduction: Shunt placement is an effective therapy for hydrocephalus. Ventriculoperitoneal shunt draining excess cerebrospinal fluid connects the cerebral ventricles to the abdominal cavity. However, intestinal obstruction may ensue as an infrequent complication of the shunt. Case presentation: A 65 years old female patient presented with abdominal pain, abdominal bloating, and ceased passage of flatus and stool for six days. She had a history of undergoing a VP shunt procedure due to midbrain obstruction and supratentorial hydrocephalus. Conservative treatment at another local hospital couldn't relieve her symptoms. Laboratory investigations revealed elevated CRP and neutrophils. CT scan showed distended small bowel loops with aerated effusion. Thus, she was admitted to our hospital and underwent an emergent laparotomy following diagnostic modalities completion. Discussion: Adhesive intestinal obstruction secondary to ventriculoperitoneal shunt is a rare but fatal shunt complication. The possible mechanisms involved include rubbing movements between the greater omentum and the catheter, cerebrospinal fluid reaction with abdominal organs, immunological rejection of the catheter, and deposition of brain tumor cells with the resultant abdominal metastatic lesions. Laparoscopic and laparotomy are warranted in the surgical management of the disease. Conclusion: A high index of suspicion for adhesive intestinal obstruction is key to timely diagnosis and treatment.

Low cholesterol is not associated with depression: data from the 2005-2018 National Health and Nutrition Examination Survey.

BACKGROUND: Although high serum cholesterol is widely recognized as a major risk factor for heart disease, the health effects of low cholesterol are less clear. Several studies have found a correlation between low cholesterol and depression, but the results are inconsistent. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 were utilized in this cross-sectional study. The analysis of the relationship between cholesterol and depression was performed at three levels: low total cholesterol, low high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol. The inclusion criteria were as follows: (1) people with low (<4.14 mmol/L) or normal (4.14-5.16 mmol/L) total cholesterol for Sample 1; people with low (<1 mmol/L) or normal (≥1 mmol/L) HDL cholesterol levels for Sample 2; and people with low (<1.8 mmol/L) or normal (1.8-3.4 mmol/L) LDL cholesterol levels for Sample 3; and (2) people who completed the Patient Health Questionnaire-9 depression scale. Age, sex, educational level, race, marital status, self-rated health, alcohol status, smoking status, body mass index (BMI), poverty income ratio, physical function, comorbidities, and prescription use were considered potential confounders. The missing data were handled by multiple imputations of chained equations. Logistic regression was used to assess the relationship between low cholesterol and depression. RESULTS: After controlling for potential confounding factors in the multivariate logistic regression, no association was observed between depression and low total cholesterol (OR=1.0, 95% CI: 0.9-1.2), low LDL cholesterol (OR=1.0, 95% CI: 0.8-1.4), or low HDL cholesterol (OR=0.9, 95% CI: 0.8-1.1). The results stratified by sex also showed no association between low total cholesterol, low LDL cholesterol, low HDL cholesterol and depression in either men or women. CONCLUSION: This population-based study did not support the assumption that low cholesterol was related to a higher risk of depression. This information may contribute to the debate on how to manage people with low cholesterol in clinical practice.

Regulation of PTEN and ovarian cancer progression by an E3 ubiquitin ligase RBCK1.

Ovarian cancer is one of the most lethal gynecologic malignancies worldwide, with the 5-year survival is less than 50%. Although some clinical achievements have been achieved, the overall survival rate has remained unchanged over the past 20 years. Therefore, it is necessary and urgent to develop the potential modifiers and therapeutic approach to improve the overall survival rate in ovarian cancer patients. RBCK1 is an RING protein E3 ubiquitin ligase, which was revealed to involve in the progression of several cancers through its ubiquitination function. In this research, we report that RBCK1 expression is significantly elevated in human ovarian cancer and strongly associated with poor patients' prognosis. RBCK1 deficiency induces cell apoptosis and inhibits cell proliferation and migration in ovarian cancer cells. In terms of molecular mechanism, we report that RBCK1 interacts with PTEN and promotes PTEN degradation in K48-linked ubiquitination. Our study suggests a new and interesting regulatory mechanism that RBCK1 facilitates PTEN degradation, which could be a new potential therapeutic target for ovarian cancer treatment.

Biological Mechanisms of S-Nitrosothiol Formation and Degradation: How Is Specificity of S-Nitrosylation Achieved?

The modification of protein cysteine residues underlies some of the diverse biological functions of nitric oxide (NO) in physiology and disease. The formation of stable nitrosothiols occurs under biologically relevant conditions and time scales. However, the factors that determine the selective nature of this modification remain poorly understood, making it difficult to predict thiol targets and thus construct informatics networks. In this review, the biological chemistry of NO will be considered within the context of nitrosothiol formation and degradation whilst considering how specificity is achieved in this important post-translational modification. Since nitrosothiol formation requires a formal one-electron oxidation, a classification of reaction mechanisms is proposed regarding which species undergoes electron abstraction: NO, thiol or S-NO radical intermediate. Relevant kinetic, thermodynamic and mechanistic considerations will be examined and the impact of sources of NO and the chemical nature of potential reaction targets is also discussed.

A Bayesian approach to tissue-fraction estimation for oncological PET segmentation.

Tumor segmentation in oncological PET is challenging, a major reason being the partial-volume effects (PVEs) that arise due to low system resolution and finite voxel size. The latter results in tissue-fraction effects (TFEs), i.e. voxels contain a mixture of tissue classes. Conventional segmentation methods are typically designed to assign each image voxel as belonging to a certain tissue class. Thus, these methods are inherently limited in modeling TFEs. To address the challenge of accounting for PVEs, and in particular, TFEs, we propose a Bayesian approach to tissue-fraction estimation for oncological PET segmentation. Specifically, this Bayesian approach estimates the posterior mean of the fractional volume that the tumor occupies within each image voxel. The proposed method, implemented using a deep-learning-based technique, was first evaluated using clinically realistic 2D simulation studies with known ground truth, in the context of segmenting the primary tumor in PET images of patients with lung cancer. The evaluation studies demonstrated that the method accurately estimated the tumor-fraction areas and significantly outperformed widely used conventional PET segmentation methods, including a U-net-based method, on the task of segmenting the tumor. In addition, the proposed method was relatively insensitive to PVEs and yielded reliable tumor segmentation for different clinical-scanner configurations. The method was then evaluated using clinical images of patients with stage IIB/III non-small cell lung cancer from ACRIN 6668/RTOG 0235 multi-center clinical trial. Here, the results showed that the proposed method significantly outperformed all other considered methods and yielded accurate tumor segmentation on patient images with Dice similarity coefficient (DSC) of 0.82 (95% CI: 0.78, 0.86). In particular, the method accurately segmented relatively small tumors, yielding a high DSC of 0.77 for the smallest segmented cross-section of 1.30 cm2. Overall, this study demonstrates the efficacy of the proposed method to accurately segment tumors in PET images.

A Novel Drug Delivery System: the Encapsulation of Naringenin in Metal-Organic Frameworks into Liposomes.

Poorly water-soluble naringenin (NAR) was selected as a model drug and loaded into the porous MOFs for the construction of NAR@ZIF-8 inclusion complex. By film dispersion method, NAR@ZIF-8 was further encapsulated into liposomes to fabricate a novel drug delivery system. Liposomes and a novel drug delivery system were established. Subsequently, the lipid-drug ratio, phospholipid-cholesterol ratio, and hydration temperature were investigated using the Box-Behnken design based the single factor experiment. The prepared liposomes system showed spherical or quasi-spherical shape, uniform particle size distribution, and complete structure. More specifically, the average particle size was 113.2 ± 1.4 nm, and zeta potential was - 7.536 ± 0.264 mV. Moreover, the drug release behaviors of NAR, NAR@ZIF-8, and NAR@ZIF-8 liposomes were explored in vitro. Compared with free NAR and NAR@ZIF-8 which exhibited a burst drug release, NAR@ZIF-8 liposomes showed a more sustained release behavior with 79.86% drug release in 72 h. In vitro cytotoxicity experiments showed that, compared with free NAR and NAR@ZIF-8, NAR@ZIF-8 liposomes exhibited higher inhibition efficiency on lung adenocarcinoma A549 cells and gastric cancer SGC-7901 cells in a concentration-dependent manner.

A "turn off-on" fluorescent nanoprobe consisting of CuInS2 quantum dots for determination of the activity of ß-glucosidase and for inhibitor screening.

A fluorescent "turn off-on" nanoprobe is described for highly sensitive and selective determination of the activity of the enzyme ß-glucosidase (ß-Glu). Firstly, cysteine modified CuInS2 quantum dots (Cys-CuInS2 QDs) were prepared from indium(III) and copper(II) salts and the presence of thiourea. The red fluorescence of the Cys-CuInS2 QDs, with excitation/emission maxima at 590/656 nm, is quenched by Cu(II). However, in the presence of ß-Glu and the cyanogenic glycoside, enzymatic hydrolysis leads to the formation of cyanide. The latter competitively binds to Cu(II) owing to its high affinity for cyanide. This restores the fluorescence of the Cys-CuInS2 QDs. Under the optimum conditions, fluorescence increases linearly in the 0.5-700 U·L-1 ß-Glu activity range. The detection limit is 0.2 U·L-1. The nanoprobe was applied to analyze spiked soil samples, and satisfactory results were obtained. The average recoveries of ß-Glu were in the range of 96-103%, and the RSD was lower than 4.0%. The fluorescent probe can also be used to screen for ß-Glu inhibitors as demonstrated for castanospermine as an example. Graphical abstractSchematic representation of the fluorescent nanoprobe for ß-glucosidase activity detection and inhibitor screening by taking advantage of the fluorescence (FL) "turn-off" and "turn-on" feature of cysteine capped CuInS2 quantum dots (Cys-CuInS2 QDs).