Preventive machine learning models incorporating health checkup data and hair mineral analysis for low bone mass identification.

Machine learning (ML) models have been increasingly employed to predict osteoporosis. However, the incorporation of hair minerals into ML models remains unexplored. This study aimed to develop ML models for predicting low bone mass (LBM) using health checkup data and hair mineral analysis. A total of 1206 postmenopausal women and 820 men aged 50 years or older at a health promotion center were included in this study. LBM was defined as a T-score below - 1 at the lumbar, femur neck, or total hip area. The proportion of individuals with LBM was 59.4% (n = 1205). The features used in the models comprised 50 health checkup items and 22 hair minerals. The ML algorithms employed were Extreme Gradient Boosting (XGB), Random Forest (RF), Gradient Boosting (GB), and Adaptive Boosting (AdaBoost). The subjects were divided into training and test datasets with an 80:20 ratio. The area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and an F1 score were evaluated to measure the performances of the models. Through 50 repetitions, the mean (standard deviation) AUROC for LBM was 0.744 (± 0.021) for XGB, the highest among the models, followed by 0.737 (± 0.023) for AdaBoost, and 0.733 (± 0.023) for GB, and 0.732 (± 0.021) for RF. The XGB model had an accuracy of 68.7%, sensitivity of 80.7%, specificity of 51.1%, PPV of 70.9%, NPV of 64.3%, and an F1 score of 0.754. However, these performance metrics did not demonstrate notable differences among the models. The XGB model identified sulfur, sodium, mercury, copper, magnesium, arsenic, and phosphate as crucial hair mineral features. The study findings emphasize the significance of employing ML algorithms for predicting LBM. Integrating health checkup data and hair mineral analysis into these models may provide valuable insights into identifying individuals at risk of LBM.

Clinical characteristics and salivary biomarkers of burning mouth syndrome.

OBJECTIVES: To investigate the clinical characteristics and salivary biomarkers in each type of burning mouth syndrome (BMS) patients. MATERIALS AND METHODS: Ninety-eight postmenopausal female patients with BMS were included. Fifty and 21 patients were assigned to the primary and secondary groups, respectively. Twenty-seven patients with both primary and secondary characteristics were assigned to the intermediate group. Comprehensive clinical characteristics and salivary biomarkers were analyzed. RESULTS: Significant differences in age, proportion of hyposalivator patients based on unstimulated whole saliva (UWS), symptom distribution, severties of burning sensation and effect of oral complaints in daily life (Eff-life), and positive symptom distress index (PSDI) were observed among the three groups. The primary group had significant higher UWS flow rate, fewer UWS hyposalivator proportions, and lesser severity of Eff-life than the secondary group. The intermediate group had significantly greater intensities of burning sensation and Eff-life and higher PSDI score than did the primary group. The primary group had significantly higher cortisol and dehydroepiandrosterone (DHEA) levels in stimulated whole saliva than did the secondary group. CONCLUSIONS: This study's findings show that clinical characteristics differentiate each BMS type. Cortisol and DHEA levels are potential salivary biomarkers for discriminating between the primary and secondary types of BMS.

Application of Machine Learning Algorithms to Predict Osteoporotic Fractures in Women.

BACKGROUND: Predicting the risk of osteoporotic fractures is vital for prevention. Traditional methods such as the Fracture Risk Assessment Tool (FRAX) model use clinical factors. This study examined the predictive power of the FRAX score and machine-learning algorithms trained on FRAX parameters. METHODS: We analyzed the data of 2,147 female participants from the Ansan cohort study. The FRAX parameters employed in this study included age, sex (female), height and weight, current smoking status, excessive alcohol consumption (>3 units/d of alcohol), and diagnosis of rheumatoid arthritis. Osteoporotic fracture was defined as one or more fractures of the hip, spine, or wrist during a 10-year observation period. Machine-learning algorithms, such as gradient boosting, random forest, decision tree, and logistic regression, were employed to predict osteoporotic fractures with a 70:30 training-to-test set ratio. We evaluated the area under the receiver operating characteristic curve (AUROC) scores to assess and compare the performance of these algorithms with the FRAX score. RESULTS: Of the 2,147 participants, 3.5% experienced osteoporotic fractures. Those with fractures were older, shorter in height, and had a higher prevalence of rheumatoid arthritis, as well as higher FRAX scores. The AUROC for the FRAX was 0.617. The machine-learning algorithms showed AUROC values of 0.662, 0.652, 0.648, and 0.637 for gradient boosting, logistic regression, decision tree, and random forest, respectively. CONCLUSION: This study highlighted the immense potential of machine-learning algorithms to improve osteoporotic fracture risk prediction in women when complete FRAX parameter information is unavailable.

Effects of Zinc Compounds on Lysozyme, Peroxidase, and α-Amylase from the Perspective of Oral Health: a Scoping Review.

Zinc has been proposed as a topical therapeutic agent for the prevention and treatment of various oral diseases. The purpose of this scoping review was to investigate the effects of zinc on the enzymatic activities of lysozyme, peroxidase, and α-amylase from the perspective of developing oral health care products and therapeutic agents for oral diseases. A comprehensive review of the scientific literature was conducted on the direct interactions of zinc with lysozyme, peroxidase, and α-amylase from various sources. Most of the reports on the effects of zinc on the enzymatic activities of lysozyme, peroxidase, and α-amylase involved enzymes derived from bacteria, fungi, animals, and plants. Studies of human salivary enzymes were scarce. Zinc was found to inhibit the enzymatic activities of lysozyme, peroxidase, and α-amylase under diverse experimental conditions. The suggested mechanism was ionic interactions between zinc and enzyme molecules. The possibility that zinc causes structural changes to enzyme molecules has also been suggested. In conclusion, for zinc to be used as an effective topical therapeutic agent for oral health, further studies on the activity of human salivary enzymes are warranted, and additional information regarding the type and concentration of effective zinc compounds is also required.

Antidepressant effects of p-coumaric acid isolated from Vaccinium bracteatum leaves extract on chronic restraint stress mouse model and antagonism of serotonin 6 receptor in vitro.

BACKGROUND: Vaccinium bracteatum Thunb. leaves (VBL) are used in traditional herbal medicines to treat various biological diseases. p-coumaric acid (CA), the main active component of VBL, has neuroprotective effects against corticosterone-induced damage in vitro. However, the effects of CA on immobility induced by chronic restraint stress (CRS) in a mouse model and 5-HT receptor activity have not been investigated. HYPOTHESIS/PURPOSE: We investigated the antagonistic effects of VBL, NET-D1602, and the three components of Gαs protein-coupled 5-HT receptors. Additionally, we identified the effects and mechanism of action of CA, the active component of NET-D1602, in the CRS-exposed model. METHODS: For in vitro analyses, we used 1321N1 cells stably expressing human 5-HT6 receptors and CHO-K1 expressing human 5-HT4 or 5-HT7 receptors cell lines to study the mechanism of action. For in vivo analyses, CRS-exposed mice were orally administered CA (10, 50, or 100 mg/kg) daily for 21 consecutive days. The effects of CA were analyzed by assessing behavioral changes using a forced swim test (FST), measuring levels of hypothalamic-pituitary-adrenal (HPA) axis-related hormones in ntial therapeutic effects as 5-HT6 receptor antagonists for neurodegenerative diseases and depressioserum, and acetylcholinesterase (AChE), monoamines, including 5-HT, dopamine, and norepinephrine, using enzyme-linked immunosorbent assay kits. The underlying molecular mechanisms of the serotonin transporter (SERT), monoamine oxidase A (MAO-A), and extracellular signal-regulated kinase (ERK)/protein kinase B (Akt)/mTORC1 signaling were detected using western blotting. RESULTS: CA was confirmed to be an active component in the antagonistic effects of NET-D1602 on 5-HT6 receptor activity through decreases in cAMP and ERK1/2 phosphorylation. Moreover, CRS-exposed mice treated with CA showed a significantly reduced immobility time in the FST. CA also significantly decreased corticosterone, corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) levels. CA enhanced 5-HT, dopamine, and norepinephrine levels in the hippocampus (HC) and prefrontal cortex (PFC) but decreased MAO-A and SERT protein levels. Similarly, CA significantly upregulated the ERK, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Akt/mTOR/p70S6K/S6 signaling pathways in both HC and the PFC. CONCLUSION: CA contained in NET-D1602 may play the antidepressant effects against CRS-induced depression-like mechanism and the selective antagonist effect of 5-HT6 receptor.

Changes in the lesion surface suggesting transformation of oral potentially malignant disorders to malignancy - a report of eight cases.

BACKGROUND: In the case of oral potentially malignant disorders (OPMD), the possibility of malignant transformation of the lesion necessitates a decision on the need for an additional biopsy at each visit. Among many clinical characteristics, change on the lesion surface is one of the important factors that determine the need for additional biopsy at each visit. The purpose of the study was to provide information on the characteristics of lesions related to malignant transformation during the follow-up period of OPMD. METHODS: Eight patients (four men and four women) with OPMD that transformed into malignancy during long-term follow-up were included and their mean age was 65.8 ± 12.4 years. Clinical information and histopathological diagnosis were investigated at the initial visit and during the long-term follow-up period. The focus was on information on changes on the lesion surface at the time the lesion was confirmed to be malignant. The period from initial diagnosis to dysplasia and from dysplasia to malignancy was also investigated. RESULTS: The OPMD diagnoses were oral lichen planus or oral lichenoid lesions (n = 2), oral leukoplakia (n = 5), and hyperplastic candidiasis (n = 1). During the follow-up period of the lesions, when dysplasia was obtained by additional biopsy, changes in the lesions consisted of an increase in the size of the white or red area. The lesion surface of the OPMD showed verrucous, papillary, exophytic, corrugated, and ulcerative changes at the time of malignancy diagnosis. The period for the initial lesion to become dysplasia, from dysplasia to malignancy, and from the initial lesion to malignancy was very variable. CONCLUSIONS: Attention should be paid to verrucous, papillary, exophytic, corrugated, and ulcerative changes on the lesion surface of OPMD. Considering that the period for OPMD to become malignant is highly variable, a longer follow-up of the lesion is necessary.

A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities.

Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody-drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target 'undruggable' Wnt signaling.

Temporomandibular disorders-related videos on YouTube are unreliable sources of medical information: A cross-sectional analysis of quality and content.

Objective: The amount of online medical information available is rapidly growing and YouTube is considered as the most popular source of healthcare information nowadays. However, no study has been conducted to comprehensively evaluate YouTube videos related to temporomandibular disorders (TMD). So this study aimed to evaluate the content and quality of YouTube videos as a source of medical information on TMD. Method: A total of 237 YouTube videos that were systematically searched using five keywords (temporomandibular disorders, tmd, temporomandibular joint, tmj, and jaw joint) were included. Included videos were categorized by purpose and source for analysis. The quality (DISCERN, Health on the Net (HON), Ensuring Quality Information for Patients (EQIP), and Global Quality Scale (GQS)) and scientific accuracy of video contents were evaluated. Results: Total content, DISCERN, HON, EQIP, and GQS scores were 7.5%, 38.9%, 35.2%, 53.0%, and 48.6% of the maximum possible score, respectively. Only 69 videos (29.1%) were considered as "useful" for patients. News media, physician, and medical source videos showed higher evaluation scores than others. Quality evaluation scores were not significantly correlated or negatively correlated with public preference indices. In the ROC curve analysis, content and DISCERN score showed above excellent discrimination ability for high-quality videos based on GQS (P < 0.001) and total score (P < 0.001). Conclusions: YouTube videos related to TMD contained low quality and scientifically inaccurate information that could negatively influence patients with TMD.

A new murine esophageal organoid culture method and organoid-based model of esophageal squamous cell neoplasia.

Organoids mimic the physiologic and pathologic events of organs. However, no consensus on esophageal organoid (EO) culture methods has been reached. Moreover, organoid models reproducing esophageal squamous cell carcinoma (ESCC) initiation have been unavailable. Herein, we sought to develop an esophageal minimum essential organoid culture medium (E-MEOM) for culturing murine EOs and establishing an early ESCC model. We formulated E-MEOM to grow EOs from a single cell with clonal expansion, maintenance, and passage. We found that EOs cultured in E-MEOM were equivalent to the esophageal epithelium by histological analysis and transcriptomic study. Trp53 knockout and Kras G12D expression in EOs induced the development of esophageal squamous neoplasia, an early lesion of ESCC. Here we propose the new formula for EO culture with minimum components and the organoid model recapitulating ESCC initiation, laying the foundation for ESCC research and drug discovery.

Prediction of treatment outcome in burning mouth syndrome patients using machine learning based on clinical data.

The purpose of this study is to apply a machine learning approach to predict whether patients with burning mouth syndrome (BMS) respond to the initial approach and clonazepam therapy based on clinical data. Among the patients with the primary type of BMS who visited the clinic from 2006 to 2015, those treated with the initial approach of detailed explanation regarding home care instruction and use of oral topical lubricants, or who were prescribed clonazepam for a minimum of 1 month were included in this study. The clinical data and treatment outcomes were collected from medical records. Extreme Gradient-Boosted Decision Trees was used for machine learning algorithms to construct prediction models. Accuracy of the prediction models was evaluated and feature importance calculated. The accuracy of the prediction models for the initial approach and clonazepam therapy was 67.6% and 67.4%, respectively. Aggravating factors and psychological distress were important features in the prediction model for the initial approach, and intensity of symptoms before administration was the important feature in the prediction model for clonazepam therapy. In conclusion, the analysis of treatment outcomes in patients with BMS using a machine learning approach showed meaningful results of clinical applicability.

Oral health-related quality of life and associated factors in patients with xerostomia.

OBJECTIVE: This study aimed to investigate clinical and demographic factors associated with oral health-related quality of life (OHRQoL) in patients with xerostomia. METHODS: Forty-one patients (55.2 ± 13.8 years) with xerostomia as a chief complaint participated in the study. Comprehensive information about clinical and demographic characteristics of the patients with xerostomia, xerostomia-related symptoms and behaviours, and xerostomia-associated complaints was investigated using a xerostomia questionnaire. Flow rates of unstimulated and stimulated whole saliva were measured. The Oral Health Impact Profile-14 (OHIP-14) score was used to assess the OHRQoL of patients. The relationships between various factors and the OHIP-14 score were assessed by simple and multiple linear regression analyses. RESULTS: The OHIP-14 score of patients with xerostomia was high (44.3 ± 13.2). Characteristics of the patients with xerostomia associated with high OHIP-14 score were the intensity of xerostomia-related symptoms, frequency of xerostomia-related behaviours and the presence of speaking difficulty. Results from multiple linear regressions found that self-reported amount of saliva in usual, everyday life (ß = 0.622, p = 0.012) and the presence of a speaking difficulty (ß = 0.348, p = 0.014) had significant adversely affected the OHRQoL in patients with xerostomia. CONCLUSIONS: Subjective perceptions of the amount of saliva in the mouth and the experience of speaking difficulty affected the OHRQoL in patients with xerostomia.

Elevated levels of urine isocitrate, hydroxymethylglutarate, and formiminoglutamate are associated with arterial stiffness in Korean adults.

Recent evidence suggests that cellular perturbations play an important role in the pathogenesis of cardiovascular diseases. Therefore, we analyzed the association between the levels of urinary metabolites and arterial stiffness. Our cross-sectional study included 330 Korean men and women. The brachial-ankle pulse wave velocity was measured as a marker of arterial stiffness. Urinary metabolites were evaluated using a high-performance liquid chromatograph-mass spectrometer. The brachial-ankle pulse wave velocity was found to be positively correlated with L-lactate, citrate, isocitrate, succinate, malate, hydroxymethylglutarate, α-ketoisovalerate, α-keto-ß-methylvalerate, methylmalonate, and formiminoglutamate among men. Whereas, among women, the brachial-ankle pulse wave velocity was positively correlated with cis-aconitate, isocitrate, hydroxymethylglutarate, and formiminoglutamate. In the multivariable regression models adjusted for conventional cardiovascular risk factors, three metabolite concentrations (urine isocitrate, hydroxymethylglutarate, and formiminoglutamate) were independently and positively associated with brachial-ankle pulse wave velocity. Increased urine isocitrate, hydroxymethylglutarate, and formiminoglutamate concentrations were associated with brachial-ankle pulse wave velocity and independent of conventional cardiovascular risk factors. Our findings suggest that metabolic disturbances in cells may be related to arterial stiffness.

PAF remodels the DREAM complex to bypass cell quiescence and promote lung tumorigenesis.

The DREAM complex orchestrates cell quiescence and the cell cycle. However, how the DREAM complex is deregulated in cancer remains elusive. Here, we report that PAF (PCLAF/KIAA0101) drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex. PAF is highly expressed in lung adenocarcinoma (LUAD) and is associated with poor prognosis. Importantly, Paf knockout markedly suppressed LUAD development in mouse models. PAF depletion induced LUAD cell quiescence and growth arrest. PAF is required for the global expression of cell-cycle genes controlled by the repressive DREAM complex. Mechanistically, PAF inhibits DREAM complex formation by binding to RBBP4, a core DREAM subunit, leading to transactivation of DREAM target genes. Furthermore, pharmacological mimicking of PAF-depleted transcriptomes inhibited LUAD tumor growth. Our results unveil how the PAF-remodeled DREAM complex bypasses cell quiescence to promote lung tumorigenesis and suggest that the PAF-DREAM axis may be a therapeutic vulnerability in lung cancer.

Oral health-related quality of life and associated factors in patients with burning mouth syndrome.

OBJECTIVE: The purpose of this study was to assess oral health-related quality of life (OHRQoL) in patients with burning mouth syndrome (BMS) and to identify clinical factors associated with OHRQoL. METHODS: Fifty-seven patients with BMS (56.4 ± 10.7 years) participated in the study. Patients underwent oral examination, laboratory tests, psychological evaluation, measurement of salivary flow rates and evaluation of clinical characteristics using a BMS questionnaire. The OHRQoL of patients was assessed using the Oral Health Impact Profile-14 (OHIP-14). RESULTS: The OHIP-14 score for patients with BMS was 38.6 ± 12.8. Patients had higher scores for the psychological discomfort and physical pain dimensions of the OHIP-14. The intensity of taste disturbance or xerostomia symptoms (ß = 0.464, P < .001), worry about symptoms (ß = 0.307, P = .020), and results of psychological evaluation (ß = 0.311, P = .026) were significantly associated with OHIP-14 score. Multiple linear regression showed that the intensity of taste disturbance or xerostomia symptoms was significantly associated with decreased OHRQoL (ß = 0.637, P = .026). CONCLUSIONS: This study suggests that severity of taste disturbance or xerostomia is an important factor that influences OHRQoL in patients with BMS.

Treatment outcomes and related clinical characteristics in patients with burning mouth syndrome.

OBJECTIVES: To evaluate the treatment outcomes of medication therapies in patients with burning mouth syndrome (BMS) and to identify the clinical characteristics that may affect the efficacy of prescribed medications. METHODS: This is a retrospective study of 769 patients with oral burning sensations. Of these patients, 420 patients diagnosed as the primary BMS received an "Initial Approach" that involved a detailed explanation about its etiopathophysiology, self-care instruction, and use of an oral lubricant. Neuropathic medications were prescribed for 277 patients who did not respond to the initial approach. Clinical characteristics, prescribed medications, and changes in intensity of oral symptoms were reviewed. RESULTS: Clonazepam was administered as the first-line medication. Alpha-lipoic acid (ALA), gabapentin, and nortriptyline were commonly administered in combination with clonazepam. More than two-thirds of the patients reported a marked improvement in oral symptoms after treatments with combination of neuropathic medications and ALA. The efficacies of the initial approach and clonazepam had significant positive associations with the initial intensity of oral symptoms and significant negative associations with depression. CONCLUSIONS: Clonazepam therapy in combination with appropriate medications was effective for managing patients with BMS. The initial intensity of oral symptoms and psychological status were significantly associated with treatment outcomes.

Blockers of Wnt3a, Wnt10a, or ß-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo.

Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/ß-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of ß-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated ß-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1ß in DRG. PAC also upregulated rAxin2 in mice. Furthermore, ß-catenin was expressed in neurons, including calcitonin gene-related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and ß-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.

TMEM9-v-ATPase Activates Wnt/ß-Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis.

BACKGROUND AND AIMS: How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. APPROACH AND RESULTS: TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain ß-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of ß-catenin, independent of HCC-associated ß-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/ß-catenin through APC stabilization and ß-catenin cytosolic retention. CONCLUSIONS: Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.

Targeting Wnt Signaling for Gastrointestinal Cancer Therapy: Present and Evolving Views.

Wnt signaling governs tissue development, homeostasis, and regeneration. However, aberrant activation of Wnt promotes tumorigenesis. Despite the ongoing efforts to manipulate Wnt signaling, therapeutic targeting of Wnt signaling remains challenging. In this review, we provide an overview of current clinical trials to target Wnt signaling, with a major focus on gastrointestinal cancers. In addition, we discuss the caveats and alternative strategies for therapeutically targeting Wnt signaling for cancer treatment.

A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.

Necrotic cell death induces melanotic mass formation in Drosophila.

The immune system protects its host from not only invading parasites and parasitoids, but also altered self tissue, including dying cells. Necrotic cells are strongly immunogenic, but in Drosophila this has not been directly addressed, due partially to the fact that knowledge about necrosis in Drosophila currently lags behind that for other models. Upon the loss of cell matrix attachment, endocycling polyploid tissues of the Drosophila larva undergo autophagy instead of apoptosis; we employed this system as a model to examine cell death modalities and immunity. Here, we report that larval fat body cells depleted of integrin undergo not only autophagy, but also necrotic cell death, and that a blockade of reaper, grim, hid, or the downstream caspases enhances necrosis. These cells elicit melanotic mass formation, an autoimmune-like response. We also show that necrosis is the main cause of melanotic mass formation in these anchorage-depleted polyploid cells.