4'-O-methylbavachalcone alleviates ischemic stroke injury by inhibiting parthanatos and promoting SIRT3.

Cerebral ischemia-reperfusion injury (CIRI) can induce massive death of ischemic penumbra neurons via oxygen burst, exacerbating brain damage. Parthanatos is a form of caspase-independent cell death involving excessive activation of PARP-1, closely associated with intense oxidative stress following CIRI. 4'-O-methylbavachalcone (MeBavaC), an isoprenylated chalcone component in Fructus Psoraleae, has potential neuroprotective effects. This study primarily investigates whether MeBavaC can act on SIRT3 to alleviate parthanatos of ischemic penumbra neurons induced by CIRI. MeBavaC was oral gavaged to the middle cerebral artery occlusion-reperfusion (MCAO/R) rats after occlusion. The effects of MeBavaC on cerebral injury were detected by the neurological deficit score and cerebral infarct volume. In vitro, PC-12 cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R), and assessed cell viability and cell injury. Also, the levels of ROS, mitochondrial membrane potential (MMP), and intracellular Ca2+ levels were detected to reflect mitochondrial function. We conducted western blotting analyses of proteins involved in parthanatos and related signaling pathways. Finally, the exact mechanism between the neuroprotection of MeBavaC and parthanatos was explored. Our results indicate that MeBavaC reduces the cerebral infarct volume and neurological deficit scores in MCAO/R rats, and inhibits the decreased viability of PC-12 cells induced by OGD/R. MeBavaC also downregulates the expression of parthanatos-related death proteins PARP-1, PAR, and AIF. However, this inhibitory effect is weakened after the use of a SIRT3 inhibitor. In conclusion, the protective effect of MeBavaC against CIRI may be achieved by inhibiting parthanatos of ischemic penumbra neurons through the SIRT3-PARP-1 axis.

HCC1, a Polygalacturonase, Regulates Chlorophyll Degradation via the Ethylene Synthesis Pathway.

Chlorophyll degradation is an important physiological process and is essential for plant growth and development. However, how chlorophyll degradation is controlled at the cellular and molecular level remains largely elusive. Pectin is a main component of the primary cell wall, and polygalacturonases (PGs) is a group of pectin-hydrolases that cleaves the pectin backbone and release oligogalacturonide. Whether and how PGs affect chlorophyll degradation metabolism and its association with ethylene (ETH) have not been reported before. Here, we report a novel function of PG in a mutant 'high chlorophyll content1' hcc1, which displayed a decrease in growth and yield. Our morphological, biochemical and genetic analyses of hcc1, knockout lines and complementation lines confirm the function of HCC1 in chlorophyll degradation. In hcc1, the PG activity, ETH content and D-galacturonic acid (D-GA) was significantly decreased and showed an increase in the thickness of the cell wall. Exogenous application of ETH and D-GA can increase ETH content and induce the expression of HCC1, which further can successfully induce the chlorophyll degradation in hcc1. Together, our data demonstrated a novel function of HCC1 in chlorophyll degradation via the ETH pathway.

3D Morphology of Different Crystal Forms in ß-Nucleated and Fiber-Sheared Polypropylene: α-Teardrops, α-Teeth, and ß-Fans.

Polymorphism of semicrystalline polymers has significant influence on their physical properties, with each form having its advantages and disadvantages. However, real-life polymer processing often results in different coexisting crystal polymorphs, and it remains a challenge to determine their shape, spatial distribution, and volume fraction. Here, i-polypropylene (i-PP) sheets containing both α- and ß-forms were prepared either by adding ß-nucleating agent or by fiber pulling-induced crystallization. By adding a compatible dye that is partially rejected from the growing crystalline aggregates (spherulites and cylindrites), we visualize the shape of these objects in 3D using two-photon fluorescence confocal microscopy. To distinguish between crystal forms, we take advantage of the difference in dye-retaining ability of the α- and ß-aggregates. Even in 2D, fluorescence microscopy (FM) distinguishes the two crystal forms better than polarized microscopy. In 3D imaging, the volume fraction and spatial distribution of α- and ß-forms in different morphological types could be determined quantitatively. Morphologies described as α-teeth, ß-fans, and α-teardrops were visualized for the first time in 3D. Furthermore, internal and surface microcracks were seen to be associated predominantly with the ß-form and around the fiber. Spatial distribution of α- and ß-forms was also determined by scanning with a synchrotron X-ray beam. Good agreement was obtained with 3D microscopy, but XRD could not match the detail obtainable by the tomography. The work demonstrates the ability of the 3D imaging method to distinguish different crystal forms and their specific morphologies.

Bazedoxifene attenuates intestinal injury in sepsis by suppressing the NF-κB/NLRP3 signaling pathways.

Acute inflammatory injury is the primary cause of sepsis, leading to various organ failures. Bazedoxifene (BAZ) has been proven to have anti-inflammatory effects. However, its effects on sepsis-induced intestinal injury are unclear. Here, we demonstrated the beneficial effects of BAZ on intestinal injury and explored the underlying mechanisms using cecal ligation and perforation (CLP)-mediated sepsis mouse model and in vitro cultured intestinal epithelial MODE-K cells. We found that BAZ elevated the survival rate of septic mice and attenuated CLP-triggered intestinal damage. BAZ inhibited intestinal inflammation and restored the impaired intestinal barriers in CLP mice. The mechanistic study in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-stimulated MODE-K cells showed that BAZ significantly downregulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1ß (IL-1ß), caspase-1, and gasdermin D (GSDMD), and markedly reduced the phosphorylation of molecules in the nuclear factor kappa B (NF-κB) pathway. Moreover, BAZ prominently rescued the decreased viability of MODE-K cells and reduced lactate dehydrogenase (LDH) release upon LPS/ATP challenge. However, BAZ did not affect the inflammasome assembly, as evidenced by the lack of changes in ASC (apoptosis speck-like protein containing a CARD) speck formation. Our results suggest that BAZ relieves inflammation and intestinal barrier function disruption by suppressing the NF-κB/NLRP3 signaling pathways. Therefore, BAZ is a potential therapeutic candidate for treating intestinal injury in sepsis.

Betulinaldehyde exhibits effective anti-tumor effects in A549 cells by regulating intracellular autophagy.

It is of great significance to find new effective drugs for an adjuvant therapy targeting lung cancer to improve the survival rate and prognosis of patients with the disease. Previous studies have confirmed that certain Chinese herbal extracts have clear anti-tumor effects, and in our preliminary study, betulinaldehyde was screened for its potential anti-tumor effects. The current study thus aimed to confirm the anti-tumor effect of betulinaldehyde, using in vitro experiments to explore its underlying molecular mechanism. It was found that betulinaldehyde treatment significantly inhibited the viability, proliferation, and migration of A549 cells in a dose-dependent manner. In addition, betulinaldehyde inhibited the activation of Akt, MAPK, and STAT3 signaling pathways in A549 cells in a time-dependent manner. More importantly, betulinaldehyde also decreased the expression level of SQSTM1 protein, increased the expression level of LC3 II, and increased the autophagy flux in A549 cells. The pretreatment of A549 cells with the autophagy inhibitor, 3-methyladenine, could partially negate the anti-tumor effects of betulinaldehyde. These findings suggest that betulinaldehyde could significantly inhibit the oncological activity of A549 cells by regulating the intracellular autophagy level, making it a potentially effective option for the adjuvant therapy used to treat lung cancer in the future.

Calcitonin gene-related peptide ameliorates sepsis-induced intestinal injury by suppressing NLRP3 inflammasome activation.

Intestinal damage has long been viewed as the primary cause of sepsis-induced multiple organ dysfunction syndrome (MODS). Previous studies have demonstrated that calcitonin gene-related peptide (CGRP) exhibits anti-inflammatory and protective effects in mice exposed to endotoxin. This study investigated whether CGRP protects against sepsis-induced intestinal damage and its underlying mechanisms. Using a murine caecal ligation and puncture (CLP) model, we observed elevated serum and intestinal CGRP levels in septic mice. CGRP knockout (KO) mice showed more severe intestinal barrier damage, excessive NLRP3 inflammasome activation and higher levels of inflammation. In vitro, we used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to activate the NLRP3 inflammasome in MODE-K murine intestinal epithelial cells. CGRP inhibited NF-κB pathway activation; prevented ASC assembly and ROS accumulation; significantly decreased NLRP3, Caspase-1 p10, and IL-1ß levels and LDH release; and increased cell viability. Treatment with an IL-1ß inhibitor or CGRP suppressed p38 MAPK and ERK1/2 pathway activation and increased ZO-1 and Occludin protein levels in LPS+ATP-treated MODE-K cells. Finally, we used the CGRP upstream agonist drug rutaecarpine (RUT) to control endogenous CGRP release in mice, and this drug demonstrated good therapeutic effects on septic intestinal injury. In conclusion, our results suggest that CGRP ameliorates sepsis-induced intestinal damage, providing valuable insights for drug development.

The characteristics and long-term outcomes of acute promyelocytic leukemia patients with early intracranial hemorrhage.

Intracranial hemorrhage (ICH) is a major cause of early death (ED) and leads to poor prognosis in acute promyelocytic leukemia (APL). We retrospectively described 27 unselected APL patients who experienced early ICH. The ED rate was 37%. The 3-year overall survival (OS) rate was 45.4%, while the 3-year OS rate of patients who survived through induction therapy was 87.5%. No patient experienced central nervous system leukemia (CNSL). Concurrent differentiation syndrome, white blood cell count, prothrombin time and D-dimer were related to death. Although the ED rate among APL patients with early ICH was high, patients with early ICH had a favorable outcome after surviving through induction therapy. CNSL was rare despite a history of ICH during induction therapy. Compared with APL patients without ICH, it seems unnecessary to administer additional measures to prevent CNSL for this subpopulation in the era of all-trans retinoic acid and arsenic trioxide, but this needs further validation in prospective trials.

The combination of early identification, chemotherapy, and autologous stem cell transplantation obtained favorable outcomes in unilateral primary adrenal lymphoma: A case report.

PURPOSE: Primary adrenal lymphoma (PAL) is an extremely rare entity, there were few cases have been reported. We report a 52-year-old female with unilateral PAL. METHODS: Case report. RESULTS: A rapid biopsy resulted in the diagnosis of diffuse large B-cell lymphoma after excluding pheochromocytoma. R-CHOP combined with CNS prophylaxis and autologous stem cell transplant (ASCT) has produced an excellent outcome. CONCLUSIONS: Primary adrenal lymphoma (PAL) is a sporadic and highly invasive malignant disease. Symptoms are atypical, making it difficult to obtain an accurate early diagnosis. Adrenal incidentaloma is usually the first clinical manifestation. Some patients may have fever, night sweats, weight loss, and lumbar and abdominal pain. Adrenal insufficiency (AI) may occur in a subset of patients. The identification of other adrenal malignancies, especially catecholamine-secreting tumors, is particularly important for early diagnosis.

A stratified therapeutic model incorporated with studies on regulatory B cells for elderly patients with newly diagnosed multiple myeloma.

OBJECTIVE: Despite the availability of new agents, elderly patients with multiple myeloma (MM) usually present with poor outcomes due to the heterogeneity of disease conditions, especially immune deficiency. Regulatory B cells (Bregs) can be involved in immune defects by exerting immune regulatory functions in MM. In order to provide more evidence-based practice for the elderly MM, the study established and assessed a stratified therapeutic model with studies on Bregs for Chinese Elderly Multiple Myeloma in 2021 (CEMM2021). METHODS: In this open-label, non-interventional, prospective study in the real world, 159 newly diagnosed MM (NDMM) patients over 65 years old were sequentially recruited and bone marrow aspirates prior to treatment were obtained to detect the ratios of Bregs by flow cytometry. RESULTS: Based on the CEMM2021 model, 147 patients had received at least one cycle of induction therapy, including bortezomib/dexamethasone (Bd) (n = 80), lenalidomide/dexamethasone (Rd) (n = 27), Bd with a third agent X (Bd + X) (n = 27), and other regimens (n = 13). The proportions of patients achieving very good partial response or better were comparable among Bd, Bd + X, and Rd groups (41.9% vs. 54.5% vs. 44.0%, p = 0.472). Besides, the progression-free survival (PFS) and overall survival (OS) were not significantly different among Rd, Bd, and Bd + X groups. Multivariable analysis showed that induction efficacy less than partial response (PR) were poor prognostic factors for PFS, while Revised-International Staging System (R-ISS) III and efficacy less than PR were poor prognostic factors for OS. This study also found that the ratios of bone marrow Bregs <10% (p = 0.036) and SUVmax of PET-CT scan >4.2 (p = 0.000) were closely correlated with OS in the elderly MM. CONCLUSIONS: For the elderly NDMM, the CEMM2021 algorithm in our center might provide a valuable reference for the guidance of therapeutic strategies, with the combination of Bregs resulting in an effective and clinically meaningful prediction in contemporary treatment.

Autologous hematopoietic stem cell transplantation followed by interleukin-2 for adult acute myeloid leukemia patients with favorable or intermediate risk after complete remission.

High-dose chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) is generally the optimal option for patients with acute myeloid leukemia (AML). However, for favorable- and intermediate-risk patients, the regimen remains less understood due to graft versus host disease (GVHD) and increased non-relapsed mortality (NRM) caused by allo-HSCT. Additionally, the benefit of maintenance therapy has not yet been conclusively proven. Here, we conducted a retrospective study on the long-term outcome of AML patients with favorable or intermediate risk who underwent autologous hematopoietic stem cell transplantation (auto-HSCT) followed by interleukin-2 (IL-2) subcutaneous injection as maintenance therapy. A total of 49 patients from 2007 to 2019 were included in our study. They all received a daunorubicin + cytarabine regimen as induction chemotherapy followed by four to six cycles of consolidation therapy with medium- or high-dose cytarabine. Once patients achieved complete remission (CR1), they started receiving auto-HSCT followed by IL-2 injections. The results showed that no patients stopped receiving IL-2 injections on account of adverse side effects, and the 5-year overall survival (OS) and leukemia-free survival (LFS) rates were 85.6 ± 5.0% and 78.5 ± 6.1%, respectively. The multivariate analysis also suggested that age, gender, initial white blood cell (WBC) count, AML subtype, cytogenetic risk, and conditioning regimen did not affect the prognosis. In conclusion, auto-HSCT followed by IL-2 injection is an effective treatment that can improve the prognosis of AML for patients with favorable or intermediate risk.

Profile and Antibiotic Pattern of Blood Stream Infections of Patients Receiving Hematopoietic Stem Cell Transplants in Southwest China.

Background: Bloodstream infection (BSI) is a serious medical issue causing non-relapsed mortality in patients receiving hematopoietic stem cell transplantations (HSCT). Methods: The characteristics of all patients receiving HSCT (autologous and allogeneic HSCT) in our hospital from 2013 to 2019 were studied. Ratios, medians, and ranges were calculated to describe categorical variables. Chi-square tests were performed to compare the difference between ratios. Results: A total of 741 patients receiving 746 HSCT procedures-including 376 allogeneic, 370 autologous, and four of both types-were included in the study. The overall incidence of BSI in post-transplantation patients was 8.8% (N = 65). Gram-negative bacteria were the most common strains each year (33.3-81.3%), and E. coli was the most frequently isolated (33.3%). Enterobacterales represented 64.9% of multidrug-resistant (MDR) bacteria, and the ratio of MDR rebounded from 25% to 100% within a year. A total of 27 patients died from BSI after HSCT, and the seven-day and 30-day death tolls were 12 and 18, respectively. MDR caused 63% of deaths among patients with BSI and the mortality rate caused by tigecycline-resistance was as high as 100%. Conclusion: Our results reveal the changing epidemiology of BSI and antibiotic resistance in patients receiving HSCT in Southwest China, as well as showing that MDR and tigecycline-resistant microorganisms should be given more attention. Thus, long-term routine microorganism epidemiological and resistance monitoring in patients undergoing HSCT should be a vital practice in future.

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma.

The non-germinal center B-cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) has poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity in B-cell malignancies, with modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL. The BGB-3111-207 study (NCT03145064) was a multicenter single-arm phase 2 study. Patients received twice-daily oral zanubrutinib, 160 mg, until disease progression or unacceptable toxicity. The primary end point was the overall response rate (ORR). Secondary end points included progression-free survival (PFS) and duration of response (DOR). Overall survival (OS) was an exploratory end point. Forty-one patients were enrolled in China after having progressed or not responded to prior therapy. At data cutoff, 4 patients continued treatment with 37 discontinuations. The median follow-up was 6.8 months, the ORR was 29.3%, and the complete response rate was 17.1%. Median DOR, PFS, and OS were 4.5, 2.8, and 8.4 months, respectively. Adverse events (AEs) leading to treatment discontinuation were reported in 4 patients, and grade ≥ 3 AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation, and/or flutter were not observed. Zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, like other BTK inhibitors, as well as a safety profile consistent with previous studies. Through retrospective biomarker testing, potential antitumor activity was observed in patients with both CD79B and MYD88 mutations, who have inferior outcomes to immunochemotherapy. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on developing mechanism-based treatment combinations and biomarker-driven patient selection.

Tanshinone IIA potentiates the efficacy of imatinib by regulating the AKT-MDM2-P53 signaling pathway in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by breakpoint cluster region-abelson leukemia virus (BCR/ABL) kinase. Targeting BCR/ABL kinase with tyrosine kinase inhibitors combined with chemotherapy is the standard first-line therapy for Ph+ ALL. Imatinib and dasatinib are the preferred agents for the treatment of Ph+ ALL. Dasatinib treatment can induce a faster and deeper remission than imatinib treatment; however, the side effects of dasatinib, especially the cardiovascular side effects, are markedly greater than those of imatinib. Patients will benefit from treatments that improve the efficacy of imatinib without increasing its side effects. The present study revealed that tanshinone IIA markedly potentiated the cytotoxic and apoptotic induction effects of imatinib by regulating the AKT-MDM2-P53 signaling pathway and inhibiting the anti-apoptotic proteins BCL2 and MCL1 apoptosis regulator, BCL2 family member in Ph+ ALL cell lines. In vitro studies, MTT assay, flow cytometry, western blotting and reverse transcription-quantitative PCR were performed in the present study to detect cell viability, cell apoptosis, protein expression and gene expression, respectively. In a Ph+ ALL mouse model, imatinib combined with tanshinone IIA also exhibited a synergistic effect on the reduction in leukemia burden without increasing the toxic side effects of imatinib. These results demonstrated that imatinib combined with tanshinone IIA might be a promising treatment strategy for patients with Ph+ ALL.

Successful prolonged cardiopulmonary resuscitation after intraoperative cardiac arrest due to povidone-iodine allergy: A case report.

BACKGROUND: Iodophor (povidone-iodine) is widely used clinically because of its broad-spectrum antibacterial effects. Although extremely rare, it may cause anaphylactic shock, which itself carries the life-threatening risk of cardiac arrest. CASE SUMMARY: We present a case in which a patient with postoperative infection went into anaphylactic shock and cardiac arrest caused by povidone-iodine during secondary surgery. The patient was successfully resuscitated by 2 h of cardiopulmonary resuscitation. CONCLUSION: This is the first known case of cardiac arrest caused by povidone-iodine allergy.

Comparison of allogeneic hematopoietic stem cell transplantation and TKI combined with chemotherapy for adult philadelphia chromosome positive acute lymphoblastic leukemia: a systematic review and meta-analysis.

OBJECTIVE: This study seeks to clarify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is necessary for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in post-remission based on a comparison with tyrosine kinase inhibitor (TKI) combined with chemotherapy. METHODS: We searched the Pubmed, Embase, and Web of Science databases and limited the date range for the studies from January 2010 to August 2020. A hazard ratio (HR) with a 95% confidence interval (CI) was employed to assess overall survival (OS) and relapse-free survival (RFS), and an odds ratio (OR) with a 95% CI was used to evaluate the ratio of non-relapsed mortality (NRM) and non-relapsed survival (NRS). All analyses were conducted with Stata software 16.0 and Revman 5.3. RESULTS: Fifteen studies, totaling 959 patients, were included in our analysis. Among those patients, 473 underwent allo-HSCT, and 486 received TKI plus chemotherapy. The pooled results showed no difference in OS between outcomes for patients receiving TKI plus chemotherapy and those treated with allo-HSCT (HR = 0.76, 95% CI [0.51-1.12], p = 0.16). Patients undergoing allo-HSCT did better than those receiving TKI plus chemotherapy regarding RFS (HR = 0.48, 95% CI [0.37-0.63], p = 0.00), and NRS (OR = 2.64, 95% CI [1.25-5.57], p = 0.00). The NRM rate of the TKI plus chemotherapy group was significantly lower than the allo-HSCT group (OR = 2.33, 95% CI [1.51-3.59], p = 0.00). CONCLUSION: TKI combined with chemotherapy can be considered a post-remission treatment option for adult Ph+ ALL patients who are ineligible for allo-HSCT. However, more prospective studies with large sample sizes should be carried out in the future.

Bowls, vases and goblets-the microcrockery of polymer and nanocomposite morphology revealed by two-photon optical tomography.

On the >1 µm scale the morphology of semicrystalline plastics like polyethylene or Nylon features spherulites, "shish-kebabs", cylinddrites and other crystalline aggregates which strongly affect mechanical and other material properties. Current imaging techniques give only a 2D picture of these objects. Here we show how they can be visualized in 3D using fluorescent labels and confocal microscopy. As a result, we see spherulites in 3D, both in neat polymers and their nanocomposites, and observe how unevenly nanoparticles and other additives are distributed in the material. Images of i-polypropylene and biodegradable poly(lactic acid) reveal previously unsuspected morphologies such as "vases" and "goblets", nonspherical "spherulites" and, unexpectedly, "shish-kebabs" grown from quiescent melt. Also surprisingly, in nanocomposite sheets spherulite nucleation is seen to be copied from one surface to another, mediated by crystallization-induced pressure drop and local melt-flow. These first results reveal unfamiliar modes of self-assembly in familiar plastics and open fresh perspectives on polymer microstructure.

Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma.

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

[Application of Automated Machine Learning Based on Radiomics Features of T2WI and RS-EPI DWI to Predict Preoperative T Staging of Rectal Cancer].

OBJECTIVE: To explore the radiomics features of T2 weighted image (T2WI) and readout-segmented echo-planar imaging (RS-EPI) plus difusion-weighted imaging (DWI), to develop an automated mahchine-learning model based on the said radiomics features, and to test the value of this model in predicting preoperative T staging of rectal cancer. METHODS: The study retrospectively reviewed 131 patients who were diagnosed with rectal cancer confirmed by the pathology results of their surgical specimens at West China Hospital of Sichuan University between October, 2017 and December, 2018. In addition, these patients had preoperative rectal MRI. Tumor regions from preoperative MRI were manually segmented by radiologists with the ITK-SNAP software from T2WI and RS-EPI DWI images. PyRadiomics was used to extract 200 features-100 from T2WI and 100 from the apparent diffusion coefficient (ADC) calculated from the RS-EPI DWI. MWMOTE and NEATER were used to resample and balance the dataset, and 13 cases of T 1-2 stage simulation cases were added. The overall dataset was divided into a training set (111 cases) and a test set (37 cases) by a ratio of 3∶1. Tree-based Pipeline Optimization Tool (TPOT) was applied on the training set to optimize model parameters and to select the most important radiomics features for modeling. Five independent T stage models were developed accordingly. Accuracy and the area under the curve ( AUC) of receiver operating characteristic (ROC) were used to pick out the optimal model, which was then applied on the training set and the original dataset to predict the T stage of rectal cancer. RESULTS: The performance of the the five T staging models recommended by automated machine learning were as follows: The accuracy for the training set ranged from 0.802 to 0.838, sensitivity, from 0.762 to 0.825, specificity, from 0.833 to 0.896, AUC, from 0.841 to 0.893, and average precision (AP) from 0.870 to 0.901. After comparison, an optimal model was picked out, with sensitivity, specificity and AUC for the training set reaching 0.810, 0.875, and 0.893, respectively. The sensitivity, specificity and AUC for the test set were 0.810, 0.813, and 0.810, respectively. The sensitivity, specificity and AUC for the original dataset were 0.810, 0.830, and 0.860, respectively. CONCLUSION: Based on the radiomics data of T2WI and RS-EPI DWI, the model established by automated machine learning showed a fairly high accuracy in predicting rectal cancer T stage.

Circ_0008542 in osteoblast exosomes promotes osteoclast-induced bone resorption through m6A methylation.

With an increasing aging society, China is the world's fastest growing markets for oral implants. Compared with traditional oral implants, immediate implants cause marginal bone resorption and increase the failure rate of osseointegration, but the mechanism is still unknown. Therefore, it is important to further study mechanisms of tension stimulus on osteoblasts and osteoclasts at the early stage of osseointegration to promote rapid osseointegration around oral implants. The results showed that exosomes containing circ_0008542 from MC3T3-E1 cells with prolonged tensile stimulation promoted osteoclast differentiation and bone resorption. Circ_0008542 upregulated Tnfrsf11a (RANK) gene expression by acting as a miR-185-5p sponge. Meanwhile, the circ_0008542 1916-1992 bp segment exhibited increased m6A methylation levels. Inhibiting the RNA methyltransferase METTL3 or overexpressing the RNA demethylase ALKBH5 reversed osteoclast differentiation and bone resorption induced by circ_0008542. Injection of circ_0008542 + ALKBH5 into the tail vein of mice reversed the same effects in vivo. Site-directed mutagenesis study demonstrated that 1956 bp on circ_0008542 is the m6A functional site with the abovementioned biological functions. In conclusion, the RNA methylase METTL3 acts on the m6A functional site of 1956 bp in circ_0008542, promoting competitive binding of miRNA-185-5p by circ_0008542, and leading to an increase in the target gene RANK and the initiation of osteoclast bone absorption. In contrast, the RNA demethylase ALKBH5 inhibits the binding of circ_0008542 with miRNA-185-5p to correct the bone resorption process. The potential value of this study provides methods to enhance the resistance of immediate implants through use of exosomes releasing ALKBH5.

Predictive Role of the Apparent Diffusion Coefficient and MRI Morphologic Features on IDH Status in Patients With Diffuse Glioma: A Retrospective Cross-Sectional Study.

PURPOSE: To evaluate isocitrate dehydrogenase (IDH) status in clinically diagnosed grade II~IV glioma patients using the 2016 World Health Organization (WHO) classification based on MRI parameters. MATERIALS AND METHODS: One hundred and seventy-six patients with confirmed WHO grade II~IV glioma were retrospectively investigated as the study set, including lower-grade glioma (WHO grade II, n = 64; WHO grade III, n = 38) and glioblastoma (WHO grade IV, n = 74). The minimum apparent diffusion coefficient (ADCmin) in the tumor and the contralateral normal-appearing white matter (ADCn) and the rADC (ADCmin to ADCn ratio) were defined and calculated. Intraclass correlation coefficient (ICC) analysis was carried out to evaluate interobserver and intraobserver agreement for the ADC measurements. Interobserver agreement for the morphologic categories was evaluated by Cohen's kappa analysis. The nonparametric Kruskal-Wallis test was used to determine whether the ADC measurements and glioma subtypes were related. By univariable analysis, if the differences in a variable were significant (P<0.05) or an image feature had high consistency (ICC >0.8; κ >0.6), then it was chosen as a predictor variable. The performance of the area under the receiver operating characteristic curve (AUC) was evaluated using several machine learning models, including logistic regression, support vector machine, Naive Bayes and Ensemble. Five evaluation indicators were adopted to compare the models. The optimal model was developed as the final model to predict IDH status in 40 patients with glioma as the subsequent test set. DeLong analysis was used to compare significant differences in the AUCs. RESULTS: In the study set, six measured variables (rADC, age, enhancement, calcification, hemorrhage, and cystic change) were selected for the machine learning model. Logistic regression had better performance than other models. Two predictive models, model 1 (including all predictor variables) and model 2 (excluding calcification), correctly classified IDH status with an AUC of 0.897 and 0.890, respectively. The test set performed equally well in prediction, indicating the effectiveness of the trained classifier. The subgroup analysis revealed that the model predicted IDH status of LGG and GBM with accuracy of 84.3% (AUC = 0.873) and 85.1% (AUC = 0.862) in the study set, and with the accuracy of 70.0% (AUC = 0.762) and 70.0% (AUC = 0.833) in the test set, respectively. CONCLUSION: Through the use of machine-learning algorithms, the accurate prediction of IDH-mutant versus IDH-wildtype was achieved for adult diffuse gliomas via noninvasive MR imaging characteristics, including ADC values and tumor morphologic features, which are considered widely available in most clinical workstations.