The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities.

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (ß-catenin dependent) and non-canonical (ß-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

Adipose-derived mesenchymal stem cells (MSCs) are a superior cell source for bone tissue engineering.

Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors, osteoinductive biofactors and biocompatible scaffold materials. Mesenchymal stem cells (MSCs) represent the most promising seed cells for bone tissue engineering. As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat, MSCs can be isolated from numerous tissues and exhibit varied differentiation potential. To identify an optimal progenitor cell source for bone tissue engineering, we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources, including immortalized mouse embryonic fibroblasts (iMEF), immortalized mouse bone marrow stromal stem cells (imBMSC), immortalized mouse calvarial mesenchymal progenitors (iCAL), and immortalized mouse adipose-derived mesenchymal stem cells (iMAD). We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro, whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair. Transcriptomic analysis revealed that, while each MSC line regulated a distinct set of target genes upon BMP9 stimulation, all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt, TGF-ß, PI3K/AKT, MAPK, Hippo and JAK-STAT pathways. Collectively, our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.

Hydrocephalus in Neurosarcoidosis: Clinical Course, Radiographic Accompaniments, and Experience with Shunting.

BACKGROUND: Hydrocephalus is an uncommon manifestation of neurosarcoidosis (7-14% of reported cohorts) that poses unique challenges to patient management. Despite being a recognized complication of neurosarcoidosis, very little is known about how hydrocephalus influences its clinical course, management, and prognosis. OBJECTIVES: To characterize hydrocephalus as a clinical manifestation of neurosarcoidosis, highlight which patients required cerebrospinal fluid (CSF) diversion, understand the mediating role of immunomodulatory treatments, and report outcomes in this cohort. METHODS: Patients with a diagnosis of neurosarcoidosis seen at Emory Healthcare [01/2011-8/2021] were included if hydrocephalus was one manifestation of their disease. Means and proportions were compared between shunted and non-shunted groups using the Wilcoxon rank-sum test for continuous variables and the Fisher's exact test for categorical variables. RESULTS: Twenty-two patients with neurosarcoidosis and hydrocephalus as one disease manifestation were included (22/214, 10.3%). Hydrocephalus was communicating in 13 (13/20, 65.0%) and obstructive in 6 patients (6/20, 30.0%), with features of both seen in 1 patient (1/20, 5.0%). Chronic presentations were typical (12/22, 54.5%) with altered sensorium, gait dysfunction, headache, and weakness being present in the majority of patients. There was a rostral-to-caudal gradient in ventriculomegaly, with the lateral ventricles most affected (20/20, 100%) and the fourth ventricle the least (12/20, 60%). Meningoventricular inflammation was the most common neuroinflammatory accompaniment (18/20, 90.0%), especially infratentorial leptomeningitis (16/20, 80.0%) and fourth ventriculitis (9/20, 45.0%). Thirteen patients (13/22, 59.1%) required ventriculoperitoneal shunts (VPS). Factors associated with shunt placement were younger age at neurosarcoidosis onset (p = 0.019) and hydrocephalus onset (p = 0.015), obstructive hydrocephalus (p = 0.043), and lateral ventriculitis (p = 0.043). In the 6 patients (6/13, 46.2%) with preceding extraventricular drain (EVD) placement, all failed to wean, including 5/6 patients who received high-dose steroids while the EVD was in place. Almost all (19/20, 95.0%) were treated with steroid-sparing agents, including nine (9/20, 45.0%) with tumor necrosis factor (TNF) inhibitors. Modified Rankin Scale score at last outcome was 3.04 (range 0-6). CONCLUSION: Patients with neurosarcoidosis and hydrocephalus experience unique challenges in the management of their disease, including the potential need for CSF diversion, in addition to traditional anti-inflammatory treatments. Younger patients, those with obstructive hydrocephalus, and those with lateral ventriculitis warrant particular consideration for VPS placement, but the decision to shunt likely remains a highly individualized one. The requirement for multiple lines of immunotherapy beyond steroids and moderate disability at last follow-up suggest hydrocephalus may reflect a more severe form of neurosarcoidosis.

Niclosamide (NA) overcomes cisplatin resistance in human ovarian cancer.

Ovarian cancer (OC) is one of the most lethal malignancies of the female reproductive system. OC patients are usually diagnosed at advanced stages due to the lack of early diagnosis. The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy, while several targeted therapies have recently been approved for maintenance treatment. The vast majority of OC patients relapse with chemoresistant tumors after an initial response. Thus, there is an unmet clinical need to develop new therapeutic agents to overcome the chemoresistance of OC. The anti-parasite agent niclosamide (NA) has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC. Here, we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant (CR) in human OC cells. To this end, we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer. We showed that NA inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis in both CR lines at a low micromole range. Mechanistically, NA inhibited multiple cancer-related pathways including AP1, ELK/SRF, HIF1, and TCF/LEF, in SKOV3CR and OVCAR8CR cells. NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells. Collectively, our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant human OC, and further clinical trials are highly warranted.

Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases.

Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Corrigendum to 'Modeling colorectal tumorigenesis using the organoids derived from conditionally immortalized mouse intestinal crypt cells (ciMICs)' [Genes Dis 8 (2021) 814-826].

[This corrects the article DOI: 10.1016/j.gendis.2021.01.004.].

Using Deep Learning to Predict Treatment Response in Patients with Hepatocellular Carcinoma Treated with Y90 Radiation Segmentectomy.

Treatment of hepatocellular carcinoma (HCC) with Y90 radioembolization segmentectomy (Y90-RE) demonstrates a tumor dose-response threshold, where dose estimates are highly dependent on accurate SPECT/CT acquisition, registration, and reconstruction. Any error can result in distorted absorbed dose distributions and inaccurate estimates of treatment success. This study improves upon the voxel-based dosimetry model, one of the most accurate methods available clinically, by using a deep convolutional network ensemble to account for the spatially variable uptake of Y90 within a treated lesion. A retrospective analysis was conducted in patients with HCC who received Y90-RE at a single institution. Seventy-seven patients with 103 lesions met the inclusion criteria: three or fewer tumors, pre- and post treatment MRI, and no prior Y90-RE. Lesions were labeled as complete (n = 57) or incomplete response (n = 46) based on 3-month post treatment MRI and divided by medical record number into a 20% hold-out test set and 80% training set with 5-fold cross-validation. Slice-wise predictions were made from an average ensemble of models and thresholds from the highest accuracy epochs across all five folds. Lesion predictions were made by thresholding all slice predictions through the lesion. When compared to the voxel-based dosimetry model, our model had a higher F1-score (0.72 vs. 0.2), higher accuracy (0.65 vs. 0.60), and higher sensitivity (1.0 vs. 0.11) at predicting complete treatment response. This algorithm has the potential to identify patients with treatment failure who may benefit from earlier follow-up or additional treatment.

Modeling lung diseases using reversibly immortalized mouse pulmonary alveolar type 2 cells (imPAC2).

BACKGROUND: A healthy alveolar epithelium is critical to the gas exchange function of the lungs. As the major cell type of alveolar epithelium, alveolar type 2 (AT2) cells play a critical role in maintaining pulmonary homeostasis by serving as alveolar progenitors during lung injury, inflammation, and repair. Dysregulation of AT2 cells may lead to the development of acute and chronic lung diseases and cancer. The lack of clinically relevant AT2 cell models hampers our ability to understand pulmonary diseases. Here, we sought to establish reversibly immortalized mouse pulmonary alveolar type 2 cells (imPAC2) and investigate their potential in forming alveolar organoids to model pulmonary diseases. METHODS: Primary mouse pulmonary alveolar cells (mPACs) were isolated and immortalized with a retroviral expression of SV40 Large T antigen (LTA). Cell proliferation and survival was assessed by crystal violet staining and WST-1 assays. Marker gene expression was assessed by qPCR, Western blotting, and/or immunostaining. Alveolar organoids were generated by using matrigel. Ad-TGF-ß1 was used to transiently express TGF-ß1. Stable silencing ß-catenin or overexpression of mutant KRAS and TP53 was accomplished by using retroviral vectors. Subcutaneous cell implantations were carried out in athymic nude mice. The retrieved tissue masses were subjected to H & E histologic evaluation. RESULTS: We immortalized primary mPACs with SV40 LTA to yield the imPACs that were non-tumorigenic and maintained long-term proliferative activity that was reversible by FLP-mediated removal of SV40 LTA. The EpCAM+ AT2-enriched subpopulation (i.e., imPAC2) was sorted out from the imPACs, and was shown to express AT2 markers and form alveolar organoids. Functionally, silencing ß-catenin decreased the expression of AT2 markers in imPAC2 cells, while TGF-ß1 induced fibrosis-like response by regulating the expression of epithelial-mesenchymal transition markers in the imPAC2 cells. Lastly, concurrent expression of oncogenic KRAS and mutant TP53 rendered the imPAC2 cells a tumor-like phenotype and activated lung cancer-associated pathways. Collectively, our results suggest that the imPAC2 cells may faithfully represent AT2 populations that can be further explored to model pulmonary diseases.

Melanoma: Molecular genetics, metastasis, targeted therapies, immunotherapies, and therapeutic resistance.

Cutaneous melanoma is a common cancer and cases have steadily increased since the mid 70s. For some patients, early diagnosis and surgical removal of melanomas is lifesaving, while other patients typically turn to molecular targeted therapies and immunotherapies as treatment options. Easy sampling of melanomas allows the scientific community to identify the most prevalent mutations that initiate melanoma such as the BRAF, NRAS, and TERT genes, some of which can be therapeutically targeted. Though initially effective, many tumors acquire resistance to the targeted therapies demonstrating the need to investigate compensatory pathways. Immunotherapies represent an alternative to molecular targeted therapies. However, inter-tumoral immune cell populations dictate initial therapeutic response and even tumors that responded to treatment develop resistance in the long term. As the protocol for combination therapies develop, so will our scientific understanding of the many pathways at play in the progression of melanoma. The future direction of the field may be to find a molecule that connects all of the pathways. Meanwhile, noncoding RNAs have been shown to play important roles in melanoma development and progression. Studying noncoding RNAs may help us to understand how resistance - both primary and acquired - develops; ultimately allow us to harness the true potential of current therapies. This review will cover the basic structure of the skin, the mutations and pathways responsible for transforming melanocytes into melanomas, the process by which melanomas metastasize, targeted therapeutics, and the potential that noncoding RNAs have as a prognostic and treatment tool.

Carboxymethyl chitosan prolongs adenovirus-mediated expression of IL-10 and ameliorates hepatic fibrosis in a mouse model.

Effective and safe liver-directed gene therapy has great promise in treating a broad range of liver diseases. While adenoviral (Ad) vectors have been widely used for efficacious in vivo gene delivery, their translational utilities are severely limited due to the short duration of transgene expression and solicitation of host immune response. Used as a promising polymeric vehicle for drug release and nucleic acid delivery, carboxymethyl chitosan (CMC) is biocompatible, biodegradable, anti-microbial, inexpensive, and easy accessible. Here, by exploiting its biocompatibility, controlled release capability and anti-inflammatory activity, we investigated whether CMC can overcome the shortcomings of Ad-mediated gene delivery, hence improving the prospect of Ad applications in gene therapy. We demonstrated that in the presence of optimal concentrations of CMC, Ad-mediated transgene expression lasted up to 50 days after subcutaneous injection, and at least 7 days after intrahepatic injection. Histologic evaluation and immunohistochemical analysis revealed that CMC effectively alleviated Ad-induced host immune response. In our proof-of-principle experiment using the CCl4-induced experimental mouse model of chronic liver damage, we demonstrated that repeated intrahepatic administrations of Ad-IL10 mixed with CMC effectively mitigated the development of hepatic fibrosis. Collectively, these results indicate that CMC can improve the prospect of Ad-mediated gene therapy by diminishing the host immune response while allowing readministration and sustained transgene expression.

Overview of Noninterpretive Artificial Intelligence Models for Safety, Quality, Workflow, and Education Applications in Radiology Practice.

Artificial intelligence has become a ubiquitous term in radiology over the past several years, and much attention has been given to applications that aid radiologists in the detection of abnormalities and diagnosis of diseases. However, there are many potential applications related to radiologic image quality, safety, and workflow improvements that present equal, if not greater, value propositions to radiology practices, insurance companies, and hospital systems. This review focuses on six major categories for artificial intelligence applications: study selection and protocoling, image acquisition, worklist prioritization, study reporting, business applications, and resident education. All of these categories can substantially affect different aspects of radiology practices and workflows. Each of these categories has different value propositions in terms of whether they could be used to increase efficiency, improve patient safety, increase revenue, or save costs. Each application is covered in depth in the context of both current and future areas of work. Keywords: Use of AI in Education, Application Domain, Supervised Learning, Safety © RSNA, 2022.

Ferroptosis as a novel form of regulated cell death: Implications in the pathogenesis, oncometabolism and treatment of human cancer.

The treatment of cancer mainly involves surgical excision supplemented by radiotherapy and chemotherapy. Chemotherapy drugs act by interfering with tumor growth and inducing the death of cancer cells. Anti-tumor drugs were developed to induce apoptosis, but some patient's show apoptosis escape and chemotherapy resistance. Therefore, other forms of cell death that can overcome the resistance of tumor cells are important in the context of cancer treatment. Ferroptosis is a newly discovered iron-dependent, non-apoptotic type of cell death that is highly negatively correlated with cancer development. Ferroptosis is mainly caused by the abnormal increase in iron-dependent lipid reactive oxygen species and the imbalance of redox homeostasis. This review summarizes the progression and regulatory mechanism of ferroptosis in cancer and discusses its possible clinical applications in cancer diagnosis and treatment.

What People Tweet about Imaging Costs.

BACKGROUND: Patients may experience adverse health outcomes when they are unable to manage medical bills. It is currently unknown, however, whether patients talk about cost in the context of medical imaging services they received. MATERIALS AND METHODS: Retrospective qualitative analysis of twitter posts related to medical imaging and cost. Tweets were extracted from twitter, inclusion and exclusion criteria were applied, and tweets were categorized as either "positive" or "negative"; none were "neutral". A qualitative thematic analysis of all included tweets was performed to develop themes and topics expressed. A single tweet may have been assigned several different codes according to its content. A random sampling of the tweets from each topic were selected by the two reviewers, verified by the remaining reviewers, and quoted (Q). RESULTS: Here, 9.8% (n = 99) of tweets relevant to medical imaging were included in the analysis. The majority had a negative sentiment (91%, n = 90) related to themes of (1) cost of care (47%, n = 42), (2) care delivery (23%, n = 21), (3) insurance Issues (23%, n = 21), and (4) need for information (7%, n = 6). A few positive tweets (9%, n = 9) were related to themes of (1) Gratitude (44%, n = 4), (2) Affordability (33%, n = 3), and (3) Better than expected (22%, n = 2). CONCLUSION: Among tweets related to medical imaging we found that 10% relate to cost and that these are overwhelmingly negative, mostly due to perceived high cost of care, deficient care delivery, and insurance issues.

Reversibly immortalized keratinocytes (iKera) facilitate re-epithelization and skin wound healing: Potential applications in cell-based skin tissue engineering.

Skin injury is repaired through a multi-phase wound healing process of tissue granulation and re-epithelialization. Any failure in the healing process may lead to chronic non-healing wounds or abnormal scar formation. Although significant progress has been made in developing novel scaffolds and/or cell-based therapeutic strategies to promote wound healing, effective management of large chronic skin wounds remains a clinical challenge. Keratinocytes are critical to re-epithelialization and wound healing. Here, we investigated whether exogenous keratinocytes, in combination with a citrate-based scaffold, enhanced skin wound healing. We first established reversibly immortalized mouse keratinocytes (iKera), and confirmed that the iKera cells expressed keratinocyte markers, and were responsive to UVB treatment, and were non-tumorigenic. In a proof-of-principle experiment, we demonstrated that iKera cells embedded in citrate-based scaffold PPCN provided more effective re-epithelialization and cutaneous wound healing than that of either PPCN or iKera cells alone, in a mouse skin wound model. Thus, these results demonstrate that iKera cells may serve as a valuable skin epithelial source when, combining with appropriate biocompatible scaffolds, to investigate cutaneous wound healing and skin regeneration.

OUHP: an optimized universal hairpin primer system for cost-effective and high-throughput RT-qPCR-based quantification of microRNA (miRNA) expression.

MicroRNAs (miRNAs or miRs) are single-stranded, ∼22-nucleotide noncoding RNAs that regulate many cellular processes. While numerous miRNA quantification technologies are available, a recent analysis of 12 commercial platforms revealed high variations in reproducibility, sensitivity, accuracy, specificity and concordance within and/or between platforms. Here, we developed a universal hairpin primer (UHP) system that negates the use of miRNA-specific hairpin primers (MsHPs) for quantitative reverse transcription PCR (RT-qPCR)-based miRNA quantification. Specifically, we analyzed four UHPs that share the same hairpin structure but are anchored with two, three, four and six degenerate nucleotides at 3'-ends (namely UHP2, UHP3, UHP4 and UHP6), and found that the four UHPs yielded robust RT products and quantified miRNAs with high efficiency. UHP-based RT-qPCR miRNA quantification was not affected by long transcripts. By analyzing 14 miRNAs, we demonstrated that UHP4 closely mimicked MsHPs in miRNA quantification. Fine-tuning experiments identified an optimized UHP (OUHP) mix with a molar composition of UHP2:UHP4:UHP6 = 8:1:1, which closely recapitulated MsHPs in miRNA quantification. Using synthetic LET7 isomiRs, we demonstrated that the OUHP-based qPCR system exhibited high specificity and sensitivity. Collectively, our results demonstrate that the OUHP system can serve as a reliable and cost-effective surrogate of MsHPs for RT-qPCR-based miRNA quantification for basic research and precision medicine.

Modeling colorectal tumorigenesis using the organoids derived from conditionally immortalized mouse intestinal crypt cells (ciMICs).

Intestinal cancers are developed from intestinal epithelial stem cells (ISCs) in intestinal crypts through a multi-step process involved in genetic mutations of oncogenes and tumor suppressor genes. ISCs play a key role in maintaining the homeostasis of gut epithelium. In 2009, Sato et al established a three-dimensional culture system, which mimicked the niche microenvironment by employing the niche factors, and successfully grew crypt ISCs into organoids or Mini-guts in vitro. Since then, the intestinal organoid technology has been used to delineate cellular signaling in ISC biology. However, the cultured organoids consist of heterogeneous cell populations, and it was technically challenging to introduce genomic changes into three-dimensional organoids. Thus, there was a technical necessity to develop a two-dimensional ISC culture system for effective genomic manipulations. In this study, we established a conditionally immortalized mouse intestinal crypt (ciMIC) cell line by using a piggyBac transposon-based SV40 T antigen expression system. We showed that the ciMICs maintained long-term proliferative activity under two-dimensional niche factor-containing culture condition, retained the biological characteristics of intestinal epithelial stem cells, and could form intestinal organoids in three-dimensional culture. While in vivo cell implantation tests indicated that the ciMICs were non-tumorigenic, the ciMICs overexpressing oncogenic ß-catenin and/or KRAS exhibited high proliferative activity and developed intestinal adenoma-like pathological features in vivo. Collectively, these findings strongly suggested that the engineered ciMICs should be used as a valuable tool cell line to dissect the genetic and/or epigenetic underpinnings of intestinal tumorigenesis.

Argonaute (AGO) proteins play an essential role in mediating BMP9-induced osteogenic signaling in mesenchymal stem cells (MSCs).

As multipotent progenitor cells, mesenchymal stem cells (MSCs) can renew themselves and give rise to multiple lineages including osteoblastic, chondrogenic and adipogenic lineages. It's previously shown that BMP9 is the most potent BMP and induces osteogenic and adipogenic differentiation of MSCs. However, the molecular mechanism through which BMP9 regulates MSC differentiation remains poorly understood. Emerging evidence indicates that noncoding RNAs, especially microRNAs, may play important roles in regulating MSC differentiation and bone formation. As highly conserved RNA binding proteins, Argonaute (AGO) proteins are essential components of the multi-protein RNA-induced silencing complexes (RISCs), which are critical for small RNA biogenesis. Here, we investigate possible roles of AGO proteins in BMP9-induced lineage-specific differentiation of MSCs. We first found that BMP9 up-regulated the expression of Ago1, Ago2 and Ago3 in MSCs. By engineering multiplex siRNA vectors that express multiple siRNAs targeting individual Ago genes or all four Ago genes, we found that silencing individual Ago expression led to a decrease in BMP9-induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs. Furthermore, we demonstrated that simultaneously silencing all four Ago genes significantly diminished BMP9-induced osteogenic and adipogenic differentiation of MSCs and matrix mineralization, and ectopic bone formation. Collectively, our findings strongly indicate that AGO proteins and associated small RNA biogenesis pathway play an essential role in mediating BMP9-induced osteogenic differentiation of MSCs.

Predictors of Successful Yttrium-90 Radioembolization Bridging or Downstaging in Patients with Hepatocellular Carcinoma.

Purpose: This study aims to identify clinical and imaging prognosticators associated with the successful bridging or downstaging to liver transplantation (LT) in patients undergoing Yttrium-90 radioembolization (Y90-RE) for hepatocellular carcinoma (HCC). Methods: Retrospectively, patients with Y90-RE naïve HCC who were candidates or potential candidates for LT and underwent Y90-RE were included. Patients were then divided into favorable (maintained or achieved Milan criteria (MC) eligibility) or unfavorable (lost eligibility or unchanged MC ineligibility) cohorts based on changes to their MC eligibility after Y90-RE. Penalized logistic regression analysis was performed to identify the significant baseline prognosticators. Results: Between 2013 and 2018, 135 patients underwent Y90-RE treatment. Among the 59 (42%) patients within MC, LT eligibility was maintained in 49 (83%) and lost in 10 (17%) patients. Within the 76 (56%) patients outside MC, eligibility was achieved in 32 (42%) and unchanged in 44 (58%). Among the 81 (60%) patients with a favorable response, 16 (20%) went on to receive LT. Analysis of the baseline characteristics revealed that lower Albumin-Bilirubin score, lower Child-Pugh class, lower Barcelona Clinic Liver Cancer stage, HCC diagnosis using dynamic contrast-enhanced imaging on CT or MRI, normal/higher albumin levels, decreased severity of tumor burden, left lobe HCC disease, and absence of HBV-associated cirrhosis, baseline abdominal pain, or fatigue were all associated with a higher likelihood of bridging or downstaging to LT eligibility (p's < 0.05). Conclusion: Certain baseline clinical and tumor characteristics are associated with the successful bridging or downstaging of potential LT candidates with HCC undergoing Y90-RE.

Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways.

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.