Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity.

The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC50 values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.

Transcriptome and small RNA analysis unveils novel insights into the C4 gene regulation in sugarcane.

MAIN CONCLUSION: This study reveals miRNA indirect regulation of C4 genes in sugarcane through transcription factors, highlighting potential key regulators like SsHAM3a. C4 photosynthesis is crucial for the high productivity and biomass of sugarcane, however, the miRNA regulation of C4 genes in sugarcane remains elusive. We have identified 384 miRNAs along the leaf gradients, including 293 known miRNAs and 91 novel miRNAs. Among these, 86 unique miRNAs exhibited differential expression patterns, and we identified 3511 potential expressed targets of these differentially expressed miRNAs (DEmiRNAs). Analyses using Pearson correlation coefficient (PCC) and Gene Ontology (GO) enrichment revealed that targets of miRNAs with positive correlations are integral to chlorophyll-related photosynthetic processes. In contrast, negatively correlated pairs are primarily associated with metabolic functions. It is worth noting that no C4 genes were predicted as targets of DEmiRNAs. Our application of weighted gene co-expression network analysis (WGCNA) led to a gene regulatory network (GRN) suggesting miRNAs might indirectly regulate C4 genes via transcription factors (TFs). The GRAS TF SsHAM3a emerged as a potential regulator of C4 genes, targeted by miR171y and miR171am, and exhibiting a negative correlation with miRNA expression along the leaf gradient. This study sheds light on the complex involvement of miRNAs in regulating C4 genes, offering a foundation for future research into enhancing sugarcane's photosynthetic efficiency.

Analysis of clinical factors impacting recurrence in myxofibrosarcoma.

Myxofibrosarcoma (MFS) is a malignant fibroblastic/myofibroblastic neoplasm with a prominent myxoid area. It has the clinical features of frequent local recurrence (LR) and occasional distant metastasis. Robust epidemiological data on MFS in China are lacking. The aim of this retrospective analysis was to determine the natural history of MFS, identify prognostic factors for recurrence and describe the real-life outcomes of MFS. We reviewed 52 patients with primary MFS from the First Affiliated Hospital of Nanjing Medical University diagnosed between 2016 and 2020. All tumors were subjected to retrospective univariate analysis for prognostic factors of the disease, including tumor size, grade, location and sex; patient age; planned operation; surgical margin; and laboratory results. The significant factors identified by univariate analysis were subsequently analyzed via multivariate analysis. Overall survival (OS), post-treatment LR and metastatic-free survival were assessed as outcomes. The median age was 61 years (range, 13-93). Fourteen (26.92%) patients exhibited low grade disease, and 38 (73.08%) exhibited high grade disease. Among the 29 males, and 23 females, 15 (28.85%) had tumors in the trunk, 37 (71.15%) had tumors in the extremities, 26 had undergone planned surgery, and 26 had unexpected unplanned operation. The margin was negative in 39 (75%) patients and positive in 13 patients (25%). The serum creatine kinase (CK) concentration was high level in 33 (63.46%) patients and low level in 19 (36.54%) patients. The serum lactate dehydrogenase (LDH) levels were low in 23 (44.23%) patients and high in 29 (55.77%) patients. LR was observed in 25 patients (48.08%), and 4 patients developed metastasis. A worse LR rate was found for patients with a low CK level (84.21%) than for those with a high CK level (27.27%) at 5 years (p < 0.05). The LR rate of patients who underwent planned surgery was lower than that of patients who underwent unplanned surgery (p < 0.05). There were significantly more patients with positive margins than patients with negative margins (92.30%, and 33.33%, respectively; p < 0.05). Moreover, superficial tumors were also associated with greater recurrence rate (2/20 [10%]) than deep tumors, (23/32 [71.86%]) [p < 0.05]. The probability of LR in patients with MFS was significantly greater in association with unplanned operations, positive margins, low serum CK levels or superficial tumor depth. These data could help identify high-risk patients; thus, more careful follow-up should be performed for higher-risk patients. Diagnosis and treatment at qualified regular medical centers can reduce the local recurrence rate of MFS.

Intramedullary Nail vs. Plate Fixation for Pathological Humeral Shaft Fracture: An Updated Narrative Review and Meta-Analysis of Surgery-Related Factors.

(1) Background: Pathological humeral shaft fracture (PHSF) is a frequently observed clinical manifestation in the later stages of tumor metastasis. Surgical interventions are typically recommended to alleviate pain and restore functionality. Intramedullary nail fixation (INF) or plate fixation (PF) is currently recommended for the treatment of PHSF. However, there is still no standard for optimal surgical treatment. Thus, we conducted a meta-analysis comparing the clinical outcomes of INF with PF for PHSF treatment. (2) Methods: We conducted searches in databases, such as Scopus, EMBASE, and PubMed, for studies published prior to May 2023. In total, nine studies with 485 patients were reviewed. (3) Results: There were no significant differences noted in the incidence of fixation failure, local recurrence, wound complication or overall complication. However, the INF group demonstrated a significantly lower incidence of postoperative radial nerve palsy than the PF group (OR, 5.246; 95% CI, 1.548-17.774; p = 0.008). A subgroup analysis indicated that there were no statistically significant differences in fixation failure or local recurrence among subgroups categorized by the design of intramedullary nail. (4) Conclusions: Considering the short life expectancy of end-stage patients, the choice of surgical method depends on the patient's individual condition, fracture and lesion patterns, the surgeon's experience, and comprehensive discussion between the surgeon and patient.

Liaw's Ellipse Anteversion Method for Distinguishing Acetabular Component Retroversion from Anteversion on Plain Radiographs.

Improper acetabulum component position is a significant risk factor for postoperative dislocation after total hip arthroplasty. Several radiographic two-dimensional methods exist for measuring acetabulum component anteversion, but they cannot distinguish between anteversion and retroversion. "Liaw's version," initially proposed as a simple mathematical standardized two-dimensional method, was modified to the computerized ellipse method, proving superior accuracy to traditional two-dimensional methods. In this article, we demonstrated its application in detecting and measuring retroverted acetabulum component. We obtained anteroposterior pelvis radiographs from a patient undergoing total hip arthroplasty on the day of surgery and 2 weeks postoperatively. The computerized ellipse method was used to measure the acetabulum component orientation. Upon comparison, the difference between θ assigned to be retroverted (9.52-8.56 = 0.96) is much smaller than the difference between θ assigned to be anteverted (23.81-18.86 = 4.95), leading us to determine retroversion. This was further confirmed by computed tomography at the 6-week follow-up. We propose that using the computerized ellipse method to measure Liaw's version can be a valuable tool in identifying acetabulum component retroversion on anteroposterior radiographs during routine postoperative follow-up and retrospective assessments of total hip arthroplasty patients.

Contrast-enhanced ultrasound guided core needle biopsy for soft tissue tumors: Accuracy and applicability.

OBJECTIVE: To evaluate the effectiveness of contrast-enhanced ultrasound (CEUS) guided core needle biopsy (CNB) in diagnosing soft tissue tumors (STTs) and to identify the conventional ultrasonography (US) features of STTs that are recommended for CEUS-guided CNB. MATERIALS AND METHODS: A retrospective study was conducted on 123 patients with surgically confirmed STTs. Before surgeries, all subjects underwent CNB under the guidance of US or CEUS. The histopathological results of surgical specimens were considered as the gold standards. A successful biopsy diagnosis was defined as the pathological subtypes obtained by biopsy consistent with the gold standard. The diagnostic yields were compared between the US and CEUS groups, and the diagnostic yields based on various conventional US features of STTs were also compared between the two groups. RESULTS: Sixty-seven cases underwent US-guided CNB and fifty-six cases underwent CEUS-guided CNB. The clinical, biopsy, and conventional US characteristics revealed no significant difference between the two groups. The diagnostic yield of the CEUS group was statistically higher than that of the US group (p = 0.011). In the CEUS group, more STTs with the anechoic areas were identified after CEUS examination (p = 0.031). Furthermore, the diagnostic yields based on the conventional US features of STTs, including deep fascia layer (p = 0.010), a maximum diameter ≥5 cm (p = 0.037), rough margin (p = 0.016), heterogeneous echotexture (p = 0.017), and absence of anechoic area (p = 0.013), were significantly different between the two groups, and the CEUS group exhibited higher diagnostic yields. CONCLUSION: CEUS-guided CNB was found to be an efficient method for STTs diagnosis. It is particularly recommended for STTs with the following conventional US features, including location in deep fascia layer, a maximum diameter ≥5 cm, rough margin, heterogeneous echotexture, or absence of anechoic area.

Comprehensive Characterization and Global Transcriptome Analysis of Human Fetal Liver Terminal Erythropoiesis.

The fetal liver (FL) is the key erythropoietic organ during fetal development, but knowledge on human FL erythropoiesis is very limited. In this study, we sorted primary erythroblasts from FL cells and performed RNA sequencing (RNA-seq) analyses. We found that temporal gene expression patterns reflected changes in function during primary human FL terminal erythropoiesis. Notably, the expression of genes enriched in proteolysis and autophagy was up-regulated in orthochromatic erythroblasts (OrthoEs), suggesting the involvement of these pathways in enucleation. We also performed RNA-seq of in vitro cultured erythroblasts derived from FL CD34+ cells. Comparison of transcriptomes between the primary and cultured erythroblasts revealed significant differences, indicating impacts of the culture system on gene expression. Notably, the expression of lipid metabolism-related genes was increased in cultured erythroblasts. We further immortalized erythroid cell lines from FL and cord blood (CB) CD34+ cells (FL-iEry and CB-iEry, respectively). FL-iEry and CB-iEry were immortalized at the proerythroblast stage and can be induced to differentiate into OrthoEs, but their enucleation ability was very low. Comparison of the transcriptomes between OrthoEs with and without enucleation capability revealed the down-regulation of pathways involved in chromatin organization and mitophagy in OrthoEs without enucleation capacity, indicating that defects in chromatin organization and mitophagy contribute to the inability of OrthoEs to enucleate. Additionally, the expression of HBE1, HBZ, and HBG2 was up-regulated in FL-iEry compared with CB-iEry, and this up-regulation was accompanied by down-regulated expression of BCL11A and up-regulated expression of LIN28B and IGF2BP1. Our study provides new insights into human FL erythropoiesis and rich resources for future studies.

A marked elevation in serum creatinine/cystatin C ratio may indicate pseudo-acute kidney injury due to urinary ascites: a case report and literature review.

BACKGROUND: Urinary ascites represents a scarcely observed pseudo-acute kidney injury in clinical settings. Protracted or missed diagnosis may hold grave ramifications for patient outcomes. CASE PRESENTATION: We reported a case involving an elderly female patient experiencing pseudo-acute kidney injury accompanied by ascites, wherein her renal dysfunction persisted despite medical intervention and hemodialysis. Urinary ascites was identified via a methylene blue test and by contrasting creatinine levels in serum and ascites. This patient's kidney function was multiple typified by a marked elevation in serum creatinine/Cystatin C ratio (> 2 L/dL), potentially serving as a clue for the clinical diagnosis of pseudo-acute kidney injury engendered by urinary ascites. CONCLUSIONS: This case suggested the potential diagnostic value of an asynchronous increase in serum creatinine and serum CysC (or an increased ratio of blood creatinine to blood CysC) in patients with pseudo-acute kidney injury.

A near-complete genome assembly of the allotetrapolyploid Cenchrus fungigraminus (JUJUNCAO) provides insights into its evolution and C4 photosynthesis.

JUJUNCAO (Cenchrus fungigraminus; 2n = 4x = 28) is a Cenchrus grass with the highest biomass production among cultivated plants, and it can be used for mushroom cultivation, animal feed, and biofuel production. Here, we report a nearly complete genome assembly of JUJUNCAO and reveal that JUJUNCAO is an allopolyploid that originated ∼2.7 million years ago (mya). Its genome consists of two subgenomes, and subgenome A shares high collinear synteny with pearl millet. We also investigated the genome evolution of JUJUNCAO and suggest that the ancestral karyotype of Cenchrus split into the A and B ancestral karyotypes of JUJUNCAO. Comparative transcriptome and DNA methylome analyses revealed functional divergence of homeologous gene pairs between the two subgenomes, which was a further indication of asymmetric DNA methylation. The three types of centromeric repeat in the JUJUNCAO genome (CEN137, CEN148, and CEN156) may have evolved independently within each subgenome, with some introgressions of CEN156 from the B to the A subgenome. We investigated the photosynthetic characteristics of JUJUNCAO, revealing its typical C4 Kranz anatomy and high photosynthetic efficiency. NADP-ME and PEPCK appear to cooperate in the major C4 decarboxylation reaction of JUJUNCAO, which is different from other C4 photosynthetic subtypes and may contribute to its high photosynthetic efficiency and biomass yield. Taken together, our results provide insights into the highly efficient photosynthetic mechanism of JUJUNCAO and provide a valuable reference genome for future genetic and evolutionary studies, as well as genetic improvement of Cenchrus grasses.

Outcomes after surgery in patients with and without recent influenza: a nationwide population-based study.

Background: The influence of recent influenza infection on perioperative outcomes is not completely understood. Method: Using Taiwan's National Health Insurance Research Data from 2008 to 2013, we conducted a surgical cohort study, which included 20,544 matched patients with a recent history of influenza and 10,272 matched patients without. The main outcomes were postoperative complications and mortality. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the complications and for mortality in patients with a history of influenza within 1-14 days or 15-30 days compared with non-influenza controls. Results: Compared with patients who had no influenza, patients with influenza within preoperative days 1-7 had increased risks of postoperative pneumonia (OR 2.22, 95% CI 1.81-2.73), septicemia (OR 1.98, 95% CI 1.70-2.31), acute renal failure (OR 2.10, 95% CI 1.47-3.00), and urinary tract infection (OR 1.45, 95% CI 1.23-1.70). An increased risk of intensive care admission, prolonged length of stay, and higher medical expenditure was noted in patients with history of influenza within 1-14 days. Conclusion: We found that there was an association between influenza within 14 days preoperatively and the increased risk of postoperative complications, particularly with the occurrence of influenza within 7 days prior to surgery.

Rapamycin antagonizes angiogenesis and lymphangiogenesis through myeloid-derived suppressor cells in corneal transplantation.

Rapamycin is an immunosuppressive drug that is widely used in the postsurgery management of transplantation. To date, the mechanism by which rapamycin reduces posttransplant neovascularization has not been fully understood. Given the original avascularity and immune privilege of the cornea, corneal transplantation is considered as an ideal model to investigate neovascularization and its effects on allograft rejection. Previously, we found that myeloid-derived suppressor cells (MDSC) prolong corneal allograft survival through suppression of angiogenesis and lymphangiogenesis. Here, we show that depletion of MDSC abolished rapamycin-mediated suppression of neovascularization and elongation of corneal allograft survival. RNA-sequencing analysis revealed that rapamycin dramatically enhanced the expression of arginase 1 (Arg1). Furthermore, an Arg1 inhibitor also completely abolished the rapamycin-mediated beneficial effects after corneal transplantation. Taken together, these findings indicate that MDSC and elevated Arg1 activity are essential for the immunosuppressive and antiangiogenic functions of rapamycin.

Kinkéliba (Combretum micranthum) Leaf Extract Alleviates Skin Inflammation: In Vitro and In Vivo Study.

Kinkéliba (Combretum micranthum, Seh-Haw in Wolof) is a popular bush tea in West African countries. Although the kinkéliba plant's leaves have been widely consumed for its nutritional and medicinal properties, its benefits on skin health potential have been practically untouched. In human epidermal primary keratinocytes, vitexin and isovitexin-rich kinkéliba extract treatment significantly (p < 0.001) enhanced up to 39.6% of the cell survival rate decreased by UV radiation irritation. The treatment of kinkéliba leaf extracts also reduced the production of UV-induced pro-inflammatory cytokines IL-6 and IL-8 by 57.6% and 42.5%, respectively (p < 0.001), which cause skin redness and skin barrier dysfunction, as well as wrinkles and collagen degradation. The anti-inflammation efficacy of kinkéliba leaf extracts might involve significant inhibition on the levels of cellular reactive oxygen species (ROS) (-70.8%, p < 0.001) and nitrotyrosine (-56.9%, p < 0.05). Further topical applications of kinkéliba leaf extract gel were found to reduce sodium lauryl sulfate (SLS)-induced skin inflammation: at D7, the skin trans-epidermal water loss (TEWL) and skin redness (a* value) were both reduced by 59.81% (p < 0.001) and 22.4% (p < 0.001), compared with D0. In vitro and in vivo data support a new topical application of the kinkéliba leaf as an effective active ingredient for the treatment of skin inflammation, as well as subsequent barrier dysfunction and inflammaging.

Comparison of robotic reduced-port and laparoscopic approaches for left-sided colorectal cancer surgery.

BACKGROUND/OBJECTIVE: The reduced-port approach can overcome the limitations of single-incision laparoscopic surgery while maintaining its advantages. Here, we compared the effects of robotic reduced-port surgery and conventional laparoscopic approaches for left-sided colorectal cancer. METHODS: Between January 2015 and December 2016, the clinicopathological characteristics and treatment outcomes of 17 patients undergoing robotic reduced-port surgery and 49 patients undergoing laparoscopic surgery for left-sided colorectal cancer were compared. RESULTS: The two groups were comparable in almost all outcome measures except for the distal resection margin, which was significantly longer in the laparoscopic group (P < 0.001). The between-group differences in reoperation, incisional hernia development, and overall and progression-free survival were nonsignificant; however, the total hospital cost was significantly higher in the robotic group than in the laparoscopic group (US$13779.6 ± US$3114.8 vs. US$8556.3 ± US$2056.7, P < 0.001). CONCLUSION: Robotic reduced-port surgery for left-sided colorectal cancer is safe and effective but more expensive with no additional benefit compared with the conventional laparoscopic approach. This observation warrants further evaluation.

Fabrication of High-Performance Colorimetric Membrane by Incorporation of Polydiacetylene into Polyarylene Ether Nitriles Electrospinning Nanofibrous Membranes.

Polyarylene ether nitrile (PEN) is a novel high-performance engineering plastic with various applications, particularly in thermoresistance-required fields. In this study, a well-known stimuli-response polydiacetylene monomer, 10, 12-pentacosadiynoic acid (PCDA), was encapsulated within electrospun PEN nanofibers to fabricate a colorimetric membrane with satisfactory thermal and corrosion resistance. To optimize the compatibility with PCDA, two PENswith distinct molecular chains were utilized: PEN−PPL and PEN−BPA. The chemical structure and elemental mapping analysis revealed that the PCDA component was successfully incorporated into the PEN fibrous. The PCDA bound significantly better to the PEN−PPL than to the PEN−BPA; due to the carboxyl groups present on the side chains of PEN−PPL, the surface was smooth and the color changed uniformly as the temperature rose. However, owing to its poor compatibility with PEN−BPA, the PCDA formed agglomerations on the fibers. The thermal analysis demonstrated that the membranes obtained after PCDA compounding maintained their excellent heat resistance. The 5% weight loss temperatures of composite nanofibrous membranes manufactured by PEN−PPL and PEN−BPA were 402 °C and 506 °C, respectively, and their glass transition temperatures were 219 °C and 169 °C, respectively, indicating that the blended membranes can withstand high temperatures. The evaluation of application performance revealed that the composite membranes exhibited good dimensional stability upon high thermal and corrosive situations. Specifically, the PEN−P−PCDA did not shrink at 170 °C. Both composite membranes were dimensionally stable when exposed to the alkali aqueous solution. However, PEN−P−PCDA is more sensitive to OH−, exhibiting color transition at pH > 8, whereas PEN−B−PCDA exhibited color transition at high OH− concentrations (pH ≥ 13), with enhanced alkali resistance stability owing to its nanofibrous architecture. This exploratory study reveals the feasibility of PEN nanofibers functionalized using PCDA as a desirable stimulus-response sensor even in high-temperature and corrosive harsh environments.

Biocompatibility and Biological Performance of Additive-Manufactured Bioabsorbable Iron-Based Porous Interference Screws in a Rabbit Model: A 1-Year Observational Study.

This study evaluated the mid-term (12-month) biomechanical, biocompatibility, and biological performance of additive-manufactured bioabsorbable iron-based interference screws (ISs). Two bioabsorbable iron IS types-manufactured using pure iron powder (iron_IS) and using pure iron powder with 0.2 wt% tricalcium phosphate (TCP_IS)-were compared with conventional metallic IS (control) using in vitro biocompatibility and degradation analyses and an in vivo animal study. The in vitro ultimate failure strength was significantly higher for iron_IS and TCP_IS than for control ISs at 3 months post-operatively; however, the difference between groups were nonsignificant thereafter. Moreover, at 3 months after implantation, iron_IS and TCP_IS increased bone volume fraction, bone surface area fraction, and percent intersection surface; the changes thereafter were nonsignificant. Iron_IS and TCP_IS demonstrated degradation over time with increased implant surface, decreased implant volume, and structure thickness; nevertheless, the analyses of visceral organs and biochemistry demonstrated normal results, except for time-dependent iron deposition in the spleen. Therefore, compared with conventional ISs, bioabsorbable iron-based ISs exhibit higher initial mechanical strength. Although iron-based ISs demonstrate high biocompatibility 12 months after implantation, their corrosive iron products may accumulate in the spleen. Because they demonstrate mechanical superiority along with considerable absorption capability after implantation, iron-based ISs may have potential applications in implantable medical-device development in the future.

WDR72 Enhances the Stemness of Lung Cancer Cells by Activating the AKT/HIF-1α Signaling Pathway.

Objectives: Lung cancer is a common malignant tumor with high morbidity and mortality rate. Lung cancer stem cells are crucial in the development of lung cancer. In this study, we investigate WD repeat-containing protein 72 (WDR72) on lung cancer cell stemness and explore its underlying mechanism. Methods: WDR72 expression was investigated in lung cancer tissues and lung cancer stem cells by Western blot and RT-qPCR. The stemness of lung cancer stem cells was verified by the sphere-forming experiment and the abundance of stem cell markers. For the purpose of determining lung cancer stem cell growth, metastasis, and apoptosis, the CCK-8 assay, colony formation, Transwell migration, and flow cytometry were carried out. The ability of tumorigenesis in vivo was explored by xenograft tumor mouse models. Results: Up-regulation of WDR72 was found in lung cancer tissues and lung cancer stem cells. WDR72 overexpression significantly activated the AKT/HIF-1α signaling pathway. Application of PI3K/AKT pathway inhibitor LY29004 was able to counteract the impacts of WDR72 upregulation on genes related to stemness, growth, migration, and apoptosis in lung cancer stem cells. The sphere formation of lung cancer stem cells was significantly diminished after inhibiting the AKT/HIF-1α pathway. The promotion of WDR72 overexpression on lung cancer stem cell proliferation and metastasis was also eliminated by LY29004 treatment. Conclusion: WDR72 activates the AKT/HIF-1α signaling pathway to enhance the stemness of lung cancer stem cells and promote the growth and metastasis of lung cancer.