PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche.

Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH-catabolic and anabolic-on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health.

An Evaluation of the Crop Preference and Phenotypic Characteristics of Ceracris kiangsu Tsai (Orthoptera: Arcypteridae) under Different Temperatures.

The yellow-spined bamboo locust (YSBL), Ceracris kiangsu Tsai, has historically had a significant impact on different bamboo varieties in East Asia and Southeast Asia. Since 2014, there have been many outbreaks of YSBL populations in Laos, and YSBLs subsequently invaded Southwest China in 2020 and 2023. However, there was limited information about the damage to staple crops. Life table parameters and fitness parameters were assessed using wheat, rice, waxy maize, and sweet maize under three different temperatures (25 °C, 30 °C, and 35 °C) in the laboratory. The results indicated that the YSBLs feeding on wheat seedlings displayed a significantly higher survival rate, a shorter developmental time, and a higher adult emergence rate compared to YSBLs feeding on the other host species at 30 °C. The developmental durations of 1st and 3rd instar YSBLs on wheat (1st: 8.21 ± 0.35 d; 3rd: 6.32 ± 0.34 d) and rice (1st: 7.19 ± 0.23 d; 3rd: 9.00 ± 0.66 d) were significantly shorter than those of 1st and 3rd instar YSBLs on waxy maize (1st: 13.62 ± 1.22 d; 3rd: 13.67 ± 6.33 d) and sweet maize (1st: 16.00 ± 1.79 d; 3rd: 18.00 ± 3.49 d) at 30 °C. The body lengths of male and female YSBLs on wheat (male: 29.52 ± 0.40 mm, female: 34.97 ± 0.45 mm) and rice (male: 28.85 ± 0.68 mm, female: 34.66 ± 0.35 mm) were significantly longer than those observed when they were fed on sweet maize (male: 25.64 ± 1.60 mm, female: 21.93 ± 6.89 mm). There were only male adults obtained on waxy maize. The phenotypic characteristics of the YSBLs feeding on rice seedlings were very close to those of the YSBLs feeding on wheat seedlings. A relatively slower decline was observed in the survival rates of YSBL nymphs on wheat and rice compared to those on waxy maize and sweet maize at 25 °C, 30 °C, and 35 °C. In short, this study implied that YSBLs prefer wheat and rice. This study is the first report of direct damage caused by the YSBL to wheat in the laboratory, and its results could be useful in improving our understanding of the host preference of the YSBL and providing strategies for the management of this pest in field crops.

Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma.

Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive lymphoid malignancy with a poor prognosis and lacks standard treatment. Targeted therapies are urgently needed. Here we systematically investigated the druggable mechanisms through chemogenomic screening and identified that Bcl-xL-specific BH3 mimetics effectively induced ENKTL cell apoptosis. Notably, the specific accumulation of Bcl-xL, but not other Bcl-2 family members, was verified in ENKTL cell lines and patient tissues. Furthermore, Bcl-xL high expression was shown to be closely associated with worse patient survival. The critical role of Bcl-xL in ENKTL cell survival was demonstrated utilizing selective inhibitors, genetic silencing, and a specific degrader. Additionally, the IL2-JAK1/3-STAT5 signaling was implicated in Bcl-xL dysregulation. In vivo, Bcl-xL inhibition reduced tumor burden, increased apoptosis, and prolonged survival in ENKTL cell line xenograft and patient-derived xenograft models. Our study indicates Bcl-xL as a promising therapeutic target for ENKTL, warranting monitoring in ongoing clinical trials by targeting Bcl-xL.

New Insights into Calorie Restriction Induced Bone Loss.

Caloric restriction (CR) is now a popular lifestyle choice due to its ability in experimental animals to improve lifespan, reduce body weight, and lessen oxidative stress. However, more and more emerging evidence suggests this treatment requires careful consideration because of its detrimental effects on the skeletal system. Experimental and clinical studies show that CR can suppress bone growth and raise the risk of fracture, but the specific mechanisms are poorly understood. Reduced mechanical loading has long been thought to be the primary cause of weight loss-induced bone loss from calorie restriction. Despite fat loss in peripheral depots with calorie restriction, bone marrow adipose tissue (BMAT) increases, and this may play a significant role in this pathological process. Here, we update recent advances in our understanding of the effects of CR on the skeleton, the possible pathogenic role of BMAT in CR-induced bone loss, and some strategies to mitigate any potential side effects on the skeletal system.

Design, synthesis and biological evaluation of novel quinazolinone derivatives as CRBN E3 ligase modulators.

CRBN E3 ligase modulators, also anteriorly called immunomodulatory drugs (IMiDs), exhibit excellent pharmacological activity by degrading cereblon (CRBN) associated multiple substrates and have become an important field for drug development. These modulators such as Thalidomide, Lenalidomide and CC-122 abduct CRBN to adhere to IKZF1/3 and other neosubstrates, and then induce the degradation of these substrates, thus retarding the further development of related diseases. Herein, we reported a series of CC-122 derivatives that inhibit the proliferation of hematological malignant tumor cell lines. Studies further confirmed that several derivatives which exhibit strong anti-proliferation effect induce the significant degradation of IKZF1/3. In addition, we found that the best compound 14 (SIAIS355035) exhibits better degradation activity and better anti-proliferation activities than CC-122, especially in diffuse large B lymphoma cell lines. Moreover, the PK properties of compound 14 are pretty promising with excellent oral bioavailability. These results clarified the SAR of CC-122 derivatives preliminarily and suggested that compound 14 has great value for further studies as an ideal novel CRBN E3 ligase modulation drug.

Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor.

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, disease recurrence after TKI discontinuation and clinical resistance mainly due to BCR-ABL mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC50 value of 2.7 nM and Dmax of 91.2% against BCR-ABL and has an IC50 value of 12 nM in BCR-ABL + K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust BCR-ABL degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded BCR-ABL and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of BCR-ABL, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting BCR-ABL and novel potential therapeutic agents for CML treatment.

Detection of wheat Fusarium head blight using UAV-based spectral and image feature fusion.

Infection caused by Fusarium head blight (FHB) has severely damaged the quality and yield of wheat in China and threatened the health of humans and livestock. Inaccurate disease detection increases the use cost of pesticide and pollutes farmland, highlighting the need for FHB detection in wheat fields. The combination of spectral and spatial information provided by image analysis facilitates the detection of infection-related damage in crops. In this study, an effective detection method for wheat FHB based on unmanned aerial vehicle (UAV) hyperspectral images was explored by fusing spectral features and image features. Spectral features mainly refer to band features, and image features mainly include texture and color features. Our aim was to explain all aspects of wheat infection through multi-class feature fusion and to find the best FHB detection method for field wheat combining current advanced algorithms. We first evaluated the quality of the two acquired UAV images and eliminated the excessively noisy bands in the images. Then, the spectral features, texture features, and color features in the images were extracted. The random forest (RF) algorithm was used to optimize features, and the importance value of the features determined whether the features were retained. Feature combinations included spectral features, spectral and texture features fusion, and the fusion of spectral, texture, and color features to combine support vector machine, RF, and back propagation neural network in constructing wheat FHB detection models. The results showed that the model based on the fusion of spectral, texture, and color features using the RF algorithm achieved the best performance, with a prediction accuracy of 85%. The method proposed in this study may provide an effective way of FHB detection in field wheat.

Inflammation down regulates stromal cell-derived factor 1α in the early phase of pulpitis.

The key to prevent pulp necrosis in the early stage of pulpitis is to promote tissue repair, which begins with cell migration. Stromal cell-derived factor 1α (SDF-1α) has been proven to promote cell migration. Related research has so far concentrated on the biological effects of SDF-1α while its expression in pulpitis is still unclear. We investigated the effect of inflammation on SDF-1α in dental pulp and the underlying regulatory mechanisms. First, rat pulpitis models were established by exposing pulp. SDF-1α was decreased on the 3rd day but increased on the 7th day. Next, lipopolysaccharide from Porphyromonas gingivalis (Pg.LPS) was applied to dental pulp cells (DPCs). Within 24 h, SDF-1α decreased, but after 48 h, it steadily increased. Similarly, SDF-1α expression in human chronic pulpitis tissues was also increased. To investigate the effect of altered SDF-1α on DPC migration, cell supernatants collected following Pg.LPS treatment were utilized to stimulate DPCs, and the number of migrated cells was correlated with changes in SDF-1α secretion. Finally, we explored the regulatory mechanisms of SDF-1α down-regulation in the early phase of pulpitis. Within 24 h, JNK/c-Jun pathway was activated in DPC inflammation. When JNK pathway was suppressed, SDF-1α rose. Furthermore, tumor necrosis factor receptor 2 (TNFR2) and apoptosis signal-regulated kinase-interacting protein 1 (AIP1) were up-regulated. Knockdown of them abolished Pg.LPS-induced activation of JNK and c-Jun(Ser63) and significantly enhanced SDF-1α. Our findings indicated that in the early phase of pulpitis, inflammation suppressed SDF-1α by up-regulating TNFR2 and AIP1, which activated JNK/c-Jun(Ser63) pathway.

Discovery of evodiamine derivatives as potential lead antifungal agents for the treatment of superficial fungal infections.

Mycosis, especially superficial fungal infections (SFIs), has been a serious threat to humans in recent years. Evodiamine (EVO), as an effective component of the Traditional Chinese Medicine Evodia rutaecarpa, has good antibacterial effects and low toxicity. In order to find out the potential therapeutic agents against SFIs, a series of EVO derivatives were synthesized and systematic evaluations of antifungal activity were carried out. Among them, compound A7 exhibited great antifungal activity with the values of MIC100 were 38, 38 and 2 µg/mL, respectively, against T. rubrum, T. mentagrophytes and C. albicans, and even stronger than that of ketoconazole (KCZ) with the values of MIC100 were 106, 106 and 3 µg/mL, respectively. Further antifungal evaluations in vitro verified that compound A7 indeed had favorable antifungal activity. Moreover, compound A7 could exert excellent antifungal effect on T. rubrum-infected guinea pigs, suggesting that A7 was an attractive molecule and could be a potential lead compound for the development of anti-fungal agents, and providing a great promising therapeutic strategy for fungal disease.

Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase I and II dual inhibitors for the therapy of liver cancer.

To explore novel topoisomerase inhibitors with high activity and druggability, 3-aryl isoquinoline alkaloids based on the corydamine modification and preliminary SARs of isoquinoline alkaloids in our previous works were re-designed. Currently, the design strategy is mainly revolved around the rigidity and flexibility of the molecular side chain and the molecular size. Consequently, not only the activity and druggability of the compound could be further improved, also the mechanism behind could been discovered. In vitro pharmacological studies, the outstanding nature with the excellent activity and the researchable depth of azepane-substituted compound 7 has been found through the vitro cytotoxicity test (IC50 = 1.93 µM in HuH7 cells and 2.10 µM in LM9 cells) and topoisomerase test. It was found that compound 7 had dual inhibitory effects on topoisomerase I and II, and its inhibitory activity on topoisomerase II is stronger than the positive drug etoposide. From the perspective of molecular docking, it had been verified that compound 7 could insert between DNA base pairs, which was consistent with the results of the DNA unwinding experiment. And the comet experiment confirmed 7 caused DNA damage. Meanwhile, compound 7 could inhibit cell proliferation, invasion and migration, and induce apoptosis by inhibiting PI3K/Akt/mTOR signaling pathway. Therefore, this study may lay a foundation for the discovery of 3-arylisoquinoline compounds with anti-liver cancer potential.

Isolation, synthesis and bioactivity evaluation of isoquinoline alkaloids from Corydalis hendersonii Hemsl. against gastric cancer in vitro and in vivo.

Isoquinoline alkaloid displays significant anti-gastric cancer effects due to its unique structure, which is attracting more and more attention for the development of anti-gastric cancer drugs. In this study, we explore the active components against gastric cancer from the Tibetan Medicine Corydalis hendersonii Hemsl, which is rich in isoquinoline alkaloids. 14 compounds including 2 previously undescribed natural products were obtained. Interestingly, an new active compound displays potent anti-gastric cancer activity. After accomplishing the total syntheses of the active compound and its derivatives, the anti-gastric cancer activity of the active compound was further investigated. In vitro experiments revealed that the active compound significantly attenuated the proliferative capacity, caused G2/M phase arrest, inhibited the cell migration and invasion, and induced cell apoptosis. Mechanistically, the active compound could increase the Bax/Bcl-2 ratio, elevate cytochrome c in the cytosol, and activate caspase-9/3, along with inactivating the upstream PI3K/Akt/mTOR signaling pathway. In addition, the active compound could also cause gastric cancer cell death by inhibiting topoisomerase I activity. More importantly, the anti-gastric cancer activity of the active compound was confirmed in MGC-803 xenograft nude mice in vivo. This work not only promotes the exploitation of Corydalis hendersonii Hemsl., but also provides some experience for discovering new entities from natural sources.

Wnt4 regulates bone metabolism through IKK-NF-κB and ROCK signaling under occlusal traumatic periodontitis.

BACKGROUND AND OBJECTIVE: Occlusal trauma is one of the most important local contributing factors of periodontitis. It has been reported that Wnt4, a noncanonical Wnt ligand, can inhibit osteoclast formation and inflammation and promote bone formation in vivo. However, the prospects of Wnt4 application in occlusal trauma and periodontitis have not yet been described. This study aimed to investigate the function and the corresponding mechanism of Wnt4 to regulate bone metabolism in occlusal trauma and periodontitis. MATERIAL AND METHODS: Osteogenic-induced MC3T3-E1 cells were treated with or without Porphyromonas gingivalis lipopolysaccharide (Pg. LPS) under cyclic uniaxial compressive stress. After treatment with mouse recombinant protein Wnt4 (rWnt4), the expression of osteogenic markers and activation of the IKK-NF-κB signaling pathway were evaluated in vitro. To investigate whether Wnt4 can promote osteogenesis via the ROCK signaling pathway, the expression of RhoA was evaluated in vitro. Finally, we evaluated the change in bone quantity and the activation of the IKK-NF-κB and ROCK signaling in mice with occlusal trauma and periodontitis to demonstrate the therapeutic efficacy of rWnt4 injection. RESULTS: Stimulation of traumatic force and Pg. LPS stimulation suppressed the expression of osteoblast markers, but their expression was rescued after rWnt4 treatment in vitro. In addition, the inhibition of the ROCK signaling pathway induced by force loading was reversed when rWnt4 was applied in vitro. Micro-CT, H&E, and TRAP staining of the mandibles showed increased bone loss in the occlusal trauma-aggravated periodontitis group, whereas it was rescued after rWnt4 injection. The expression levels of IκBα and p65 were upregulated in occlusal trauma and periodontitis-bearing mice, whereas the expression levels of Runx2 and RhoA were downregulated. After rWnt4 injection, remarkably upregulation of Runx2 and RhoA expression was observed in occlusal trauma and periodontitis- bearing mice. CONCLUSION: Wnt4 not only inhibits IKK-NF-κB signaling but also activates ROCK signaling to inhibit osteoclast formation and promote bone regeneration in occlusal trauma and periodontitis-bearing mice.

Discovery of novel BCR-ABL PROTACs based on the cereblon E3 ligase design, synthesis, and biological evaluation.

Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia.

EDTA Promotes the Mineralization of Dental Pulp In Vitro and In Vivo.

INTRODUCTION: Dentin regeneration is one of the main goals of vital pulp treatment in which the biological properties of dental pulp cells (DPCs) need to be considered. In our previous study, we showed that EDTA could enhance the stromal cell-derived factor 1 alpha-induced migration of DPCs. The purpose of this study was to explore the effects of EDTA on the mineralization of dental pulp in vitro and in vivo. METHODS: DPCs were obtained from human premolars or third molars. Alkaline phosphatase assays and alizarin red S staining were used to examine the degree of differentiation and mineralized nodule formation of DPCs. Real-time polymerase chain reaction and Western blot analysis were performed to detect the messenger RNA and protein expressions of mineralization-related markers in DPCs. Extracellular-regulated protein kinase and Smad inhibitors were used to study the roles of these 2 signaling pathways in this process. In addition, pulp exposures were created on 18 premolars of 2 beagle dogs (>12 months) using a high-speed dental handpiece. The experimental group (n = 9) was treated with 12% EDTA for 5 minutes, and the control group (n = 9) was treated with sterile saline for the same duration. Mineral trioxide aggregate was used for direct pulp capping followed by glass ionomer cement sealing. Samples were collected 3 months later, and the regenerated dentin was assessed by micro-computed tomographic and histologic analyses. RESULTS: Exposure to 12% EDTA promoted the activity of alkaline phosphatase, the formation of mineralized nodules, and the messenger RNA and protein expressions of mineralization-related markers in DPCs. Furthermore, the process of 12% EDTA enhancing the differentiation of DPCs was mediated by the extracellular-regulated protein kinase 1/2 signaling pathway and inhibited by the Smad2/3 signaling pathway. In vivo, compared with the control group, more regenerated dentin that had fewer tunnel defects was formed in the 12% EDTA-treated group. CONCLUSIONS: Our results showed that 12% EDTA could promote the mineralization of dental pulp in vitro and in vivo.

COX5A over-expression protects cortical neurons from hypoxic ischemic injury in neonatal rats associated with TPI up-regulation.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) represents as a major cause of neonatal morbidity and mortality. However, the underlying molecular mechanisms in brain damage are still not fully elucidated. This study was conducted to determine the specific potential molecular mechanism in the hypoxic-ischemic induced cerebral injury. METHODS: Here, hypoxic-ischemic (HI) animal models were established and primary cortical neurons were subjected to oxygen-glucose deprivation (OGD) to mimic HIE model in vivo and in vitro. The HI-induced neurological injury was evaluated by Zea-longa scores, Triphenyte-trazoliumchloride (TTC) staining the Terminal Deoxynucleotidyl Transferased Utp Nick End Labeling (TUNEL) and immunofluorescent staining. Then the expression of Cytochrome c oxidase subunit 5a (COX5A) was determined by immunohistochemistry, western blotting (WB) and quantitative real time Polymerase Chain Reaction (qRT-PCR) techniques. Moreover, HSV-mediated COX5A over-expression virus was transducted into OGD neurons to explore the role of COX5A in vitro, and the underlying mechanism was predicted by GeneMANIA, then verified by WB and qRT-PCR. RESULTS: HI induced a severe neurological dysfunction, brain infarction, and cell apoptosis as well as obvious neuron loss in neonatal rats, in corresponding to the decrease on the expression of COX5A in both sides of the brain. What's more, COX5A over-expression significantly promoted the neuronal survival, reduced the apoptosis rate, and markedly increased the neurites length after OGD. Moreover, Triosephosephate isomerase (TPI) was predicted as physical interactions with COX5A, and COX5A over-expression largely increased the expressional level of TPI. CONCLUSIONS: The present findings suggest that COX5A plays an important role in promoting neurological recovery after HI, and this process is related to TPI up-regulation.

Traumatic compressive stress inhibits osteoblast differentiation through long chain non-coding RNA Dancr.

BACKGROUND: Occlusal trauma is an important local contributing factor aggravating periodontal pocket and alveolar bone absorption in periodontal diseases. Our previous studies have found that occlusal trauma inhibited osteogenic differentiation through nuclear factor (NF)-κB signaling. To further investigate the underlying mechanism, the aim of this study was to explore the role of long chain non-coding differentiation antagonizing non-protein coding RNA (Dancr) in the inhibitory effect of traumatic stress on osteoblast differentiation. METHODS: We took the MC3T3-E1 cells as object in vitro research and stimulated cells with simple stress load, Dancr-siRNA + stress load, Dancr overexpression-plasmid + stress load. Quantitative real-time polymerase chain reaction was used to detect the RNA expression levels of Dancr, alkaline phosphatase (Alp) and Runt-related transcription factor 2 (Runx2). The protein expressions of Alp and Runx2 were tested by Western blot and the activity of Alp was qualitatively demonstrated by Alp staining. In addition, Western blot was performed to investigate the role of Dancr in affecting NF-κB signaling pathway. RESULTS: Traumatic compressive stress inhibited the expressions of Alp, Runx2, andDancr in MC3T3-E1 cells. Stress-induced inhibition of osteoblast differentiation was promoted after silencing Dancr. Overexpression of Dancr could alleviate the inhibitory effect of traumatic force on osteoblast differentiation to some extent. Furthermore, NF-κB signaling was activated after silencing Dancr, and the activated effect of traumatic force on NF-κB signaling could be alleviated through overexpression of Dancr to some extent. CONCLUSION: Traumatic compressive stress can indirectly activate the NF-κB signaling through downregulation of Dancr, thereby inhibiting osteogenic differentiation.

Physician code creep after the initiation of outpatient volume control program and implications for appropriate ICD-10-CM coding.

BACKGROUND: Most studies on the physician code creep (i.e., changes in case mix record-keeping practices to improve reimbursement) have focused on episodes (inpatient hospitalizations or outpatient procedures). Little is known regarding changes in diagnostic coding practices for better reimbursement among a fixed cohort of patients with chronic diseases. METHODS: To examine whether physicians in tertiary medical centers changed their coding practices after the initiation of the Outpatient Volume Control Program (OVCP) in Taiwan, we conducted a retrospective observational study of four patient cohorts (two interventions and two controls) from January 2016 to September 2017 in Taiwan. The main outcomes were the number of outpatient visits with four coding practices: 1) OVCP monitoring code recorded as primary diagnosis; 2) OVCP monitoring code recorded as secondary diagnosis; 3) non-OVCP monitoring code recorded as primary diagnosis; 4) non-OVCP monitoring code recorded as secondary diagnosis. RESULTS: The percentage change of the number of visits with coding practice 1 between 2016Q1 and 2017Q3 was - 74% for patients with hypertension and - 73% with diabetes in tertiary medical centers and - 23% and - 17% in clinics, respectively. By contrast, the percentage changes of coding practice 3 were + 73% for patients with hypertension and + 46% for patients with diabetes in tertiary medical centers and - 19% and - 2% in clinics, respectively. CONCLUSIONS: Physician code creep occurred after the initiation of the OVCP. Education regarding appropriate outpatient coding for physicians will be relatively effective when proper coding is related to reimbursement.

Identification of Fusarium Head Blight in Winter Wheat Ears Using Continuous Wavelet Analysis.

Fusarium head blight in winter wheat ears produces the highly toxic mycotoxin deoxynivalenol (DON), which is a serious problem affecting human and animal health. Disease identification directly on ears is important for selective harvesting. This study aimed to investigate the spectroscopic identification of Fusarium head blight by applying continuous wavelet analysis (CWA) to the reflectance spectra (350 to 2500 nm) of wheat ears. First, continuous wavelet transform was used on each of the reflectance spectra and a wavelet power scalogram as a function of wavelength location and the scale of decomposition was generated. The coefficient of determination R2 between wavelet powers and the disease infestation ratio were calculated by using linear regression. The intersections of the top 5% regions ranking in descending order based on the R2 values and the statistically significant (p-value of t-test < 0.001) wavelet regions were retained as the sensitive wavelet feature regions. The wavelet powers with the highest R2 values of each sensitive region were retained as the initial wavelet features. A threshold was set for selecting the optimal wavelet features based on the coefficient of correlation R obtained via the correlation analysis among the initial wavelet features. The results identified six wavelet features which include (471 nm, scale 4), (696 nm, scale 1), (841 nm, scale 4), (963 nm, scale 3), (1069 nm, scale 3), and (2272 nm, scale 4). A model for identifying Fusarium head blight based on the six wavelet features was then established using Fisher linear discriminant analysis. The model performed well, providing an overall accuracy of 88.7% and a kappa coefficient of 0.775, suggesting that the spectral features obtained using CWA can potentially reflect the infestation of Fusarium head blight in winter wheat ears.

Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL+ leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL+ leukemia.