IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress.

OBJECTIVES: The aim of this study was to investigate the effect of 4µ8c, an inhibitor targeting the endoplasmic reticulum stress-associated factor IRE1α, on macrophage polarization in an experimental model of diabetic periodontitis through ex vivo experiments. MATERIALS AND METHODS: Local alveolar bone parameters were evaluated using Micro-CT following intraperitoneal administration of 4µ8c in mice with experimental diabetic periodontitis. Surface markers indicating macrophage polarization were identified using immunofluorescence. In vitro experiments were performed employing bone marrow-derived macrophages and gingival fibroblasts. Macrophage polarization was determined using flow cytometry. Principal impacted signaling pathways were identified through Western blot analysis. RESULTS: Results from both in vitro and in vivo experiments demonstrated that 4µ8c mitigated alveolar bone resorption and inflammation in mice with diabetic periodontitis. Furthermore, it modulated macrophage polarization towards the M2 phenotype and augmented M2 macrophage polarization through the MAPK signaling pathway. CONCLUSIONS: These findings suggest that inhibiting IRE1α can modulate macrophage polarization and alleviate ligature-induced diabetic periodontitis via the MAPK signaling pathway. This unveils a novel mechanism, offering a scientific foundation for the treatment of experimental diabetic periodontitis.

Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Developmental endothelial locus-1 promotes osteogenic differentiation and alveolar bone regeneration in experimental periodontitis with type 2 diabetes mellitus.

OBJECTIVES: This study sought to explore the role of developmental endothelial locus-1 (DEL-1) in osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and investigate the therapeutic effect of DEL-1 in ligature-induced experimental periodontitis with type 2 diabetes mellitus (T2DM). BACKGROUND: T2DM is a significant risk factor for periodontitis. Treatment modalities for periodontitis with T2DM are being explored. DEL-1 is a versatile protein that can modulate the different stages of inflammatory diseases including periodontitis. The direct effect of DEL-1 on osteogenic differentiation of PDLSCs in periodontitis with T2DM is poorly understood. METHODS: Primary hPDLSCs were isolated from periodontal ligament tissue and identified by flow cytometry. In osteogenesis experiments, alkaline phosphatase (ALP), Alizarin Red staining and western blot were used to assess the osteogenic effect of DEL-1 on hPDLSCs in high glucose and inflammation environments. The mouse model of ligature-induced experimental periodontitis was established. H&E and Masson's trichrome staining were used to assess the change of periodontal tissue after local periodontal injection of DEL-1. Immunohistochemical staining was used to evaluate osteogenic-related protein expression. RESULTS: hPDLSCs expressed mesenchymal stem cell (MSC)-specific surface markers and were negative for hematopoietic cell surface markers. hPDLSCs had the potential for multidirectional differentiation. DEL-1 could enhance the osteogenic differentiation of hPDLSCs in high glucose and inflammation environments, although it did not return to the control level. Histological staining showed that DEL-1 contributed to alveolar bone regeneration and osteogenic-related protein expression, but the degree of improvement in T2DM mice was lower than in non-T2DM mice. CONCLUSIONS: In summary, we demonstrated that DEL-1 could promote osteogenic differentiation of hPDLSCs in high glucose and inflammation environment and rescue alveolar bone loss in experimental periodontitis with T2DM, which could provide a novel therapeutic target for periodontitis with T2DM.

Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin.

BACKGROUND: Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N6-methyladenosine (m6A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m6A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m6A modification mechanism in diabetes-associated periodontitis. METHODS: Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M6A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining. RESULTS: Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m6A level in total RNA. FTO knockdown increased the m6A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m6A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling. CONCLUSIONS: AGEs impaired BMSCs osteogenesis by regulating SOST in an m6A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.

Mechanical loading and autophagy: A study on the BoNT-A injection-induced condylar cartilage degeneration.

Botulinum toxin A (BoNT-A) has emerged as a treatment option for temporomandibular disorder (TMD). By injecting BoNT-A into the masseter muscle, it is possible to reduce mechanical loading on the temporomandibular joint (TMJ). However, numerous prior studies have indicated excessive reduction in mechanical loading can have detrimental effects on TMJ cartilage. This study proposes that autophagy, a process influenced by mechanical loading, could play a role in BoNT-A-induced mandibular condyle cartilage degeneration. To explore this hypothesis, we employed both BoNT-A injection and an excessive biting model to induce variations in mechanical loading on the condyle cartilage of C57BL/6 mice, thereby simulating an increase and decrease in mechanical loading, respectively. Results showed a significant reduction in cartilage thickness and downregulation of Runt-related transcription factor 2 (Runx2) expression in chondrocytes following BoNT-A injection. In vitro experiments demonstrated that the reduction of Runx2 expression in chondrocytes is associated with autophagy, possibly dependent on decreased YAP expression induced by low mechanical loading. This study reveals the potential involvement of the YAP/LC3/Runx2 signaling pathway in BoNT-A mediated mandibular condylar cartilage degeneration.

Comparative Efficacy of Venetoclax-Based Combination Therapies and Other Therapies in Treatment-Naive Patients With Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy: A Network Meta-Analysis.

OBJECTIVES: This network meta-analysis (NMA) assessed the efficacy of venetoclax (VEN) + azacitidine (AZA) and VEN + low-dose cytarabine (LDAC) compared with AZA, LDAC, and decitabine monotherapies and best supportive care (BSC) in adults with untreated acute myeloid leukemia ineligible for intensive chemotherapy. METHODS: A systematic literature review and feasibility assessment was conducted to select phase III randomized controlled trials for inclusion in the NMA. Complete remission + complete remission with incomplete blood count recovery and overall survival (OS) were compared using a Bayesian fixed-effects NMA. Treatments were ranked using surface under the cumulative ranking curves (SUCRAs) with higher values indicating a higher likelihood of being effective. RESULTS: A total of 1140 patients across 5 trials were included. VEN + LDAC (SUCRA 91.4%) and VEN + AZA (87.5%) were the highest ranked treatments for complete remission + complete remission with incomplete blood count recovery. VEN + LDAC was associated significantly higher response rates versus AZA (odds ratio 5.64), LDAC (6.39), and BSC (23.28). VEN + AZA was also associated significantly higher response rates than AZA (5.06), LDAC (5.74), and BSC (20.68). In terms of OS, VEN + AZA (SUCRA: 95.2%) and VEN + LDAC (75.9%) were the highest ranked treatments. VEN + AZA was associated with significant improvements in OS compared with AZA (hazard ratio 0.66), LDAC (0.57), and BSC (0.37), and VEN + LDAC was associated with significant improvements in OS compared with LDAC (0.70) and BSC (0.46). CONCLUSIONS: VEN + AZA and VEN + LDAC demonstrated improved efficacy compared with alternative therapies among treatment-naive patients with acute myeloid leukemia ineligible for intensive chemotherapy.

Real-World Treatment Patterns and Economic Burden Following First-Line Trastuzumab in Patients with Metastatic Gastric Cancer in the USA.

BACKGROUND: Trastuzumab in combination with chemotherapy is the standard first-line (1L) treatment for HER2+ metastatic gastric cancer (mGC) in the USA. OBJECTIVE: This study characterizes the real-world treatment patterns, healthcare resource use (HRU), and costs in patients with HER2+ mGC post-1L trastuzumab before approval of fam-trastuzumab deruxtecan-nxki. PATIENTS AND METHODS: This retrospective study used the IQVIA PharMetrics® Plus Database (October 2014-September 2019) to identify adults with HER2+ mGC who discontinued trastuzumab-based regimens in 1L. Patient characteristics, second-line (2L) treatment patterns, and treatment duration were summarized. HRU and costs before and after discontinuation of 1L trastuzumab-based regimens as well as during 2L treatment were described. RESULTS: Of the 190 HER2+mGC patients who discontinued 1L trastuzumab-based regimens, 136 (71.58%) initiated 2L treatments. Trastuzumab-based regimens were the most common in 2L (50.74%), followed by ramucirumab + paclitaxel (19.85%). The median time to 2L discontinuation was 2.37 months. During a mean follow-up of 9.8 months, mean per-patient-per-month (PPPM) healthcare costs post-1L trastuzumab-based regimens were higher in patients receiving 2L treatment than those without subsequent treatment (US$25,178 vs. US$14,812). The mean PPPM cost during 2L treatment was US$30,838, primarily driven by outpatient infusion costs (US$22,262). CONCLUSIONS: The short duration of 2L treatment observed in this study is consistent with a lack of effective treatments post-1L trastuzumab prior to 2020. Re-use of trastuzumab treatment was common despite its limited efficacy and high treatment cost. The findings highlight the unmet medical needs and substantial burden faced by patients with HER2 +mGC previously treated with trastuzumab.

Oxidative stress-related biomarkers in chronic periodontitis patients with or without type 2 diabetes: A systematic review and meta-analysis.

OBJECTIVE: The purpose of this meta-analysis was to look at the differences in oxidative stress (OS) biomarkers between type 2 diabetes mellitus with chronic periodontitis (DMCP) and chronic periodontitis (CP) patients. BACKGROUND: Oxidative stress has been shown to be a key pathogenic component in DMCP. However, it is unclear whether oxidative stress levels differ in periodontitis patients with or without diabetes. METHOD: A systematic search was conducted on PubMed, Cochrane, and Embase databases. Studies of DMCP participants were used as the experimental group and CP participants were used as the control group. Results are expressed as mean effects. RESULTS: Of a total of 1989 articles, 19 met the inclusion criteria. We found the levels of catalase (CAT) levels were reduced in the DMCP group compared with the CP group. However, there was no significant difference in the levels of superoxide dismutase (SOD), total antioxidant capacity (TAOC) malondialdehyde (MDA), and glutathione (GSH) between the two groups. And high heterogeneity was observed in some of the studies evaluated. CONCLUSION: Despite the limitations of this study, our results support the theory that there is an association between T2DM and the levels of OS-related biomarkers, especially CAT, in CP subjects, suggesting that OS plays an important role in the pathogenesis and development of DMCP.

Bone regeneration strategies based on organelle homeostasis of mesenchymal stem cells.

The organelle modulation has emerged as a crucial contributor to the organismal homeostasis. The mesenchymal stem cells (MSCs), with their putative functions in maintaining the regeneration ability of adult tissues, have been identified as a major driver to underlie skeletal health. Bone is a structural and endocrine organ, in which the organelle regulation on mesenchymal stem cells (MSCs) function has most been discovered recently. Furthermore, potential treatments to control bone regeneration are developing using organelle-targeted techniques based on manipulating MSCs osteogenesis. In this review, we summarize the most current understanding of organelle regulation on MSCs in bone homeostasis, and to outline mechanistic insights as well as organelle-targeted approaches for accelerated bone regeneration.

Hyperglycemia Aggravates Periodontitis via Autophagy Impairment and ROS-Inflammasome-Mediated Macrophage Pyroptosis.

Macrophage pyroptosis drives the secretion of IL-1ß, which has been recently reported to be a featured salivary biomarker for discriminating periodontitis in the presence of diabetes. This study aimed to explore whether macrophage pyroptosis plays a role in the development of diabetes mellitus-periodontitis, as well as potential therapeutic strategies. By establishing a model of experimental diabetes mellitus-periodontitis in rats, we found that IL-1ß and gasdermin D were highly expressed, leading to aggravated destruction of periodontal tissue. MCC950, a potent and selective molecule inhibitor of the NLRP3 inflammasome, effectively inhibited macrophage pyroptosis and attenuated alveolar bone losses in diabetes mellitus-periodontitis. Consistently, in vitro, high glucose could induce macrophage pyroptosis and thus promoted IL-1ß production in macrophages stimulated by lipopolysaccharide. In addition, autophagy blockade by high glucose via the mTOR-ULK1 pathway led to severe oxidative stress response in macrophages stimulated by lipopolysaccharide. Activation of autophagy by rapamycin, clearance of mitochondrial ROS by mitoTEMPO, and inhibition of inflammasome by MCC950 could significantly reduce macrophage pyroptosis and IL-1ß secretion. Our study demonstrates that hyperglycemia promotes IL-1ß production and pyroptosis in macrophages suffered by periodontal microbial stimuli. Modulation of autophagy activity and specific targeting of the ROS-inflammasome pathway may offer promising therapeutic strategies to alleviate diabetes mellitus-periodontitis.

Real-world Outcomes Associated With Poly(ADP-ribose) Polymerase Inhibitor Monotherapy Maintenance in Patients With Primary Advanced Ovarian Cancer.

OBJECTIVE: This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC). METHODS: Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses. RESULTS: Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA- mutated disease (not reached vs 11.4 mo), BRCA- wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo). CONCLUSIONS: Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS.

Suppressing STAT3 activation impairs bone formation during maxillary expansion and relapse

Abstract Objectives The mid-palatal expansion technique is commonly used to correct maxillary constriction in dental clinics. However, there is a tendency for it to relapse, and the key molecules responsible for modulating bone formation remain elusive. Thus, this study aimed to investigate whether signal transducer and activator of transcription 3 (STAT3) activation contributes to osteoblast-mediated bone formation during palatal expansion and relapse. Methodology In total, 30 male Wistar rats were randomly allocated into Ctrl (control), E (expansion only), and E+Stattic (expansion plus STAT3-inhibitor, Stattic) groups. Micro-computed tomography, micromorphology staining, and immunohistochemistry of the mid-palatal suture were performed on days 7 and 14. In vitro cyclic tensile stress (10% magnitude, 0.5 Hz frequency, and 24 h duration) was applied to rat primary osteoblasts and Stattic was administered for STAT3 inhibition. The role of STAT3 in mechanical loading-induced osteoblasts was confirmed by alkaline phosphatase (ALP), alizarin red staining, and western blots. Results The E group showed greater arch width than the E+Stattic group after expansion. The differences between the two groups remained significant after relapse. We found active bone formation in the E group with increased expression of ALP, COL-I, and Runx2, although the expression of osteogenesis-related factors was downregulated in the E+stattic group. After STAT3 inhibition, expansive force-induced bone resorption was attenuated, as TRAP staining demonstrated. Furthermore, the administration of Stattic in vitro partially suppressed tensile stress-enhanced osteogenic markers in osteoblasts. Conclusions STAT3 inactivation reduced osteoblast-mediated bone formation during palatal expansion and post-expansion relapse, thus it may be a potential therapeutic target to treat force-induced bone formation.

Identification of cross-talk pathways and ferroptosis-related genes in periodontitis and type 2 diabetes mellitus by bioinformatics analysis and experimental validation.

Purpose: There is a bidirectional relationship between periodontitis and type 2 diabetes mellitus (T2DM). The aim of this study was to further explore the pathogenesis of this comorbidity, screen out ferroptosis-related genes involved in the pathological process, and predict potential drug targets to develop new therapeutic strategies. Methods: Common cross-talk genes were identified from periodontitis datasets (GSE16134, GSE10334 and GSE106090) and T2DM databases (DisGeNET and GeneCard). Then, GO and KEGG enrichment analyses, PPI network analysis and hub gene identification were performed. The association between ferroptosis and periodontitis with T2DM was investigated by Pearson correlation analysis. Core ferroptosis-related cross-talk genes were identified and verified by qRT-PCR. Potential drugs targeting these core genes were predicted via DGIDB. Results: In total, 67 cross-talk genes and two main signalling pathways (immuno-inflammatory pathway and AGE-RAGE signalling pathway) were identified. Pearson correlation analysis indicated that ferroptosis served as a crucial target in the pathological mechanism and treatment of periodontitis with T2DM. IL-1ß, IL-6, NFE2L2 and ALOX5 were identified as core ferroptosis-related genes and the qRT-PCR detection results were statistically different. In total, 13 potential drugs were screened out, among which, Echinacea and Ibudilast should be developed first. Conclusions: This study contributes to a deeper understanding of the common pathogenesis of periodontitis and T2DM and provides new insights into the role of ferroptosis in this comorbidity. In addition, two drugs with potential clinical application value were identified. The potential utility of these drugs requires further experimental investigation.

Irisin Promotes Osteogenesis by Modulating Oxidative Stress and Mitophagy through SIRT3 Signaling under Diabetic Conditions.

Advanced glycation end products (AGEs) accumulate in the bone tissue of patients with diabetes mellitus, resulting in oxidative stress, poor bone healing, or regeneration. Irisin, a novel exercise-induced myokine, is involved in the regulation of bone metabolism. However, the effects of irisin on adipose-derived stem cell (ASC) osteogenic differentiation and bone healing under diabetic conditions remain poorly understood. ASCs were obtained from inguinal fat of Sprague-Dawley rats and treated with different concentrations of AGEs and irisin. Cell proliferation, apoptosis, and osteogenic differentiation abilities of ASCs were detected. To explore the regulatory role of sirtuin 3 (SIRT3), ASCs were transfected with lentivirus-mediated SIRT3 overexpression or knockdown vectors. Next, we investigated mitochondrial functions, mitophagy, and mitochondrial biogenesis in different groups. Moreover, SOD2 acetylation and potential signaling pathways were assessed. Additionally, a diabetic rat model was used to evaluate the effect of irisin on bone healing in calvarial critical-sized defects (CSDs) in vivo. Our results showed that irisin incubation mitigated the inhibitory effects of AGEs on ASCs by increasing cell viability and promoting osteogenesis. Moreover, irisin modulated mitochondrial membrane potential, intracellular ROS levels, mitochondrial O2 ·- status, ATP generation, complex I and IV activities, mitophagy, and mitochondrial biogenesis via a SIRT3-mediated pathway under AGEs exposure. Furthermore, in calvarial CSDs of diabetic rats, transplantation of gels encapsulating irisin-pretreated ASCs along with irisin largely enhanced bone healing. These findings suggest that irisin attenuates AGE-induced ASC dysfunction through SIRT3-mediated maintenance of oxidative stress homeostasis and regulation of mitophagy and mitochondrial biogenesis. Thus, our studies shed new light on the role of irisin in promoting the ASC osteogenesis and targeting SIRT3 as a novel therapeutic intervention strategy for bone regeneration under diabetic conditions.

Costs per patient achieving remission with venetoclax-based combinations in newly diagnosed patients with acute myeloid leukemia ineligible for intensive induction chemotherapy.

BACKGROUND: Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC), received confirmatory approval in 2020 by the US Food and Drug Administration for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged 75 years or older or who are ineligible for intensive induction chemotherapy. The economic value associated with response to venetoclax combinations compared with other treatments for this patient population has not been comprehensively evaluated. OBJECTIVE: To assess the cost per patient achieving remission with venetoclax combination therapies, compared with other therapies for newly diagnosed patients with AML who are ineligible for intensive induction chemotherapy, from a US third-party payer perspective. METHODS: The analysis used treatment effect estimates (ie, complete remission [CR] + CR with incomplete blood count recovery [CRi]) from a network meta-analysis and annual cost estimates from a prior budget impact model. The model considered the total cost of care including the costs of drug and administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management when patients discontinued active treatment. Costs per patient achieving CR + CRi associated with venetoclax + azacitidine, venetoclax + LDAC, azacitidine, decitabine, LDAC, and best supportive care (ie, treatment given with the intent to maximize quality of life without specific antileukemic intent, such as blood transfusion products and antibiotics) were calculated as the annual total cost of care per patient divided by the CR + CRi rate. All costs were adjusted to 2020 US dollars. RESULTS: Venetoclax combination therapies were estimated to have substantially lower costs per patient achieving CR + CRi (venetoclax + azacitidine: $473,960; venetoclax + LDAC: $428,071) than alternative treatments. Azacitidine was estimated to have the the highest cost per patient achieving CR + CRi ($1,197,438), followed by best supportive care ($869,849), LDAC ($689,101), and decitabine ($594,074). A pair-wise matrix of the difference between therapies estimated that both venetoclax + azacitidine and venetoclax + LDAC were associated with significantly lower costs per patient achieving CR + CRi than azacitidine (by $723,477 and $769,367, respectively) and LDAC (by $215,141 and $261,030; all P < 0.05). CONCLUSIONS: From a US third-party payer perspective, venetoclax in combination with azacitidine or LDAC was estimated to be associated with a significantly lower cost per patient achieving CR + CRi than azacitidine or LDAC among newly diagnosed patients with AML ineligible for intensive chemotherapy. DISCLOSURES: This research was supported by AbbVie Inc. and Genentech. The sponsors helped design the study, interpret the data, and draft the manuscript. Drs Bui and Kapustyan are employees of and have equity ownership in AbbVie; Dr Choi was an employee of AbbVie during the study's conduct and has equity ownership. Ms Ma and Dr Montez are employees of and have equity ownership in Genentech. Drs Song and Chai, Ms Yin, and Dr Betts are employees of Analysis Group, Inc., which has received funding from AbbVie and Genentech for the conduct of this research. Dr LeBlanc reports personal fees for consulting or advisory boards from AbbVie, Agios/Servier, AstraZeneca, Amgen, Astellas, BlueNote, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Genentech, GSK, Pfizer, and Seattle Genetics; royalties from UpToDate; speakers bureau fees from Agios/Servier, AbbVie, and BMS/Celgene; and grants and/or research contracts from the American Cancer Society, AstraZeneca, BMS, Jazz Pharmaceuticals, and Seattle Genetics.

Predicting the risk of dental implant loss using deep learning.

AIM: To investigate the feasibility of predicting dental implant loss risk with deep learning (DL) based on preoperative cone-beam computed tomography. MATERIALS AND METHODS: Six hundred and three patients who underwent implant surgery (279 high-risk patients who did and 324 low-risk patients who did not experience implant loss within 5 years) between January 2012 and January 2020 were enrolled. Three models, a logistic regression clinical model (CM) based on clinical features, a DL model based on radiography features, and an integrated model (IM) developed by combining CM with DL, were developed to predict the 5-year implant loss risk. The area under the receiver operating characteristic curve (AUC) was used to evaluate the model performance. Time to implant loss was considered for both groups, and Kaplan-Meier curves were created and compared by the log-rank test. RESULTS: The IM exhibited the best performance in predicting implant loss risk (AUC = 0.90, 95% confidence interval [CI] 0.84-0.95), followed by the DL model (AUC = 0.87, 95% CI 0.80-0.92) and the CM (AUC = 0.72, 95% CI 0.63-0.79). CONCLUSIONS: Our study offers preliminary evidence that both the DL model and the IM performed well in predicting implant fate within 5 years and thus may greatly facilitate implant practitioners in assessing preoperative risks.

C-reactive protein perturbs alveolar bone homeostasis: An experimental study of periodontitis and diabetes in the rat.

AIM: To explore the role of C-reactive protein (CRP) in periodontitis and diabetes and its mechanism in alveolar bone homeostasis. MATERIALS AND METHODS: In vivo, normal, and Crp knockout (KO) rats were randomly divided into control, diabetes, periodontitis, and diabetes and periodontitis groups, respectively. The diabetes model was established using a high-fat diet combined with streptozotocin injection. The periodontitis model was established by ligature combined with lipopolysaccharide (LPS) injection. Alveolar bones were analysed using micro-computed tomography, histology, and immunohistochemistry. In vitro, human periodontal ligament cells (hPDLCs) were treated with LPS and high glucose. CRP knockdown lentivirus or CRP overexpression adenovirus combined with a PI3K/AKT signalling inhibitor or agonist were used to explore the regulatory mechanism of CRP in osteogenesis and osteoclastogenesis of hPDLCs, as evidenced by alkaline phosphatase staining, Western blot, and quantitative polymerase chain reaction. RESULTS: In periodontitis and diabetes, CRP KO decreased the alveolar bone loss and the expression levels of osteoclastogenic markers, while increasing the expression levels of osteogenic markers. CRP constrained osteogenesis while promoting the osteoclastogenesis of hPDLCs via PI3K/AKT signalling under high glucose and pro-inflammatory conditions. CONCLUSIONS: CRP inhibits osteogenesis and promotes osteoclastogenesis via PI3K/AKT signalling under diabetic and pro-inflammatory conditions, thus perturbing alveolar bone homeostasis.

Bioinspired Andrias davidianus-Derived wound dressings for localized drug-elution.

Local drug delivery has received increasing attention in recent years. However, the therapeutic efficacy of local delivery of drugs is still limited under certain scenarios, such as in the oral cavity or in wound beds after resection of tumors. In this study, we introduce a bioinspired adhesive hydrogel derived from the skin secretions of Andrias davidianus (SSAD) as a wound dressing for localized drug elution. The hydrogel was loaded with aminoguanidine or doxorubicin, and its controlled drug release and healing-promoting properties were verified in a diabetic rat palatal mucosal defect model and a C57BL/6 mouse melanoma-bearing model, respectively. The results showed that SSAD hydrogels with different pore sizes could release drugs in a controllable manner and accelerate wound healing. Transcriptome analyses of the palatal mucosa suggested that SSAD could significantly upregulate pathways linked to cell adhesion and extracellular matrix deposition and had the ability to recruit keratinocyte stem cells to defect sites. Taken together, these findings indicate that property-controllable SSAD hydrogels could be a promising biofunctional wound dressing for local drug delivery and promotion of wound healing.

Low-intensity pulsed ultrasound enhances bone marrow-derived stem cells-based periodontal regenerative therapies.

BACKGROUND: Alveolar bone loss is one of the most common consequence for periodontitis, which is a major obstacle in periodontal regeneration. Bone marrow stromal cells (BMSCs) have shown significant promise in the treatment of various disease, which also contribute to the natural bone repair process. Low-intensity pulsed ultrasound (LIPUS) is a therapeutic ultrasound used in our previous studies to promotes alveolar bone regeneration. In addition, LIPUS was found to be a promising method to enhance mesenchymal stromal cell-based therapies. In the current study, we have investigated the effects of LIPUS combined with BMSCs therapies on BMSCs homing and its potential to promote alveolar bone regeneration. METHODS: BMSCs were isolated from rat and characterized by multilineages differentiation assay. Then these cells were labeled with luciferase and green fluorescent protein (GFP) by lentivirus in vitro. Periodontal bone defect was made on the mesial area of the maxillary first molar in rats. A total of 1 × 106 Luc-GFP labeled BMSCs were injected into rat tail vein. Bioluminescence imaging was utilized to track BMSCs in vivo. The rats were sacrificed eight weeks after surgery and the samples were harvested. Micro-computed tomography (Micro-CT) was performed to evaluate alveolar bone regeneration. Paraffin sections were made and subject to hematoxylin-eosin staining, masson staining and immunohistochemistry staining. RESULTS: BMSCs display a fibroblast-like morphology and can differentiate into adipocytes or osteoblasts under appropriate condition. The transfected BMSCs are strongly positive for GFP express. Bioluminescence imaging showed that most of BMSCs were trapped in the lung. A small portion BMSCs were homed to the alveolar bone defect area in BMSCs group, while more cells were observed in BMSCs/LIPUS group compare to other groups on day 3 and 7. Micro-CT results showed that BMSCs/LIPUS group resulted in more new bone formation than other groups. Immunohistochemical results showed higher expression of COL-I and osteopontin in BMSCs/LIPUS group compared with the other groups. CONCLUSIONS: These results suggested that LIPUS can enhance BMSCs-based periodontal alveolar bone regeneration. This study provides new insights into how LIPUS might provide therapeutic benefits by promoting BMSCs homing.