Radiogenomic-based multiomic analysis reveals imaging intratumor heterogeneity phenotypes and therapeutic targets.

Intratumor heterogeneity (ITH) profoundly affects therapeutic responses and clinical outcomes. However, the widespread methods for assessing ITH based on genomic sequencing or pathological slides, which rely on limited tissue samples, may lead to inaccuracies due to potential sampling biases. Using a newly established multicenter breast cancer radio-multiomic dataset (n = 1474) encompassing radiomic features extracted from dynamic contrast-enhanced magnetic resonance images, we formulated a noninvasive radiomics methodology to effectively investigate ITH. Imaging ITH (IITH) was associated with genomic and pathological ITH, predicting poor prognosis independently in breast cancer. Through multiomic analysis, we identified activated oncogenic pathways and metabolic dysregulation in high-IITH tumors. Integrated metabolomic and transcriptomic analyses highlighted ferroptosis as a vulnerability and potential therapeutic target of high-IITH tumors. Collectively, this work emphasizes the superiority of radiomics in capturing ITH. Furthermore, we provide insights into the biological basis of IITH and propose therapeutic targets for breast cancers with elevated IITH.

Using a CT-based scale to evaluate disease extension and the resectability of locally advanced thyroid cancer.

OBJECTIVES: To establish a computed tomography (CT)-based scale to evaluate the resectability of locally advanced thyroid cancer. METHODS: This twin-centre retrospective study included 95 locally advanced thyroid cancer patients from the 1st centre as the training cohort and 31 patients from the 2nd centre as the testing cohort, who were categorised into the resectable and unresectable groups. Three radiologists scored the CT scans of each patient by evaluating the extension to the recurrent laryngeal nerve (RLN), trachea, oesophagus, artery, vein, soft tissue, and larynx. A 14-score scale (including all comprised structures) and a 12-score scale (excluding larynx) were developed. Receiver-operating characteristic (ROC) analysis was used to evaluate the performance of the scales. Stratified fivefold cross-validation and external verification were used to validate the scale. RESULTS: In the training cohort, compromised RLN (p < 0.001), trachea (p = 0.001), oesophagus (p = 0.002), artery (p < 0.001), vein (p = 0.005), and soft tissue (p < 0.001) were predictors for unresectability, while compromised larynx (p = 0.283) was not. The 12-score scale (AUC = 0.882, 95%CI: 0.812-0.952) was not inferior to the 14-score scale (AUC = 0.891, 95%CI: 0.823-0.960). In subgroup analysis, the AUCs of the 12-score scale were 0.826 for treatment-naïve patients and 0.976 for patients with prior surgery. The 12-score scale was further validated with a fivefold cross-validation analysis, with an overall accuracy of 78.9-89.4%. Finally, external validation using the testing cohort showed an AUC of 0.875. CONCLUSIONS: The researchers built a CT-based 12-score scale to evaluate the resectability of locally advanced thyroid cancer. Validation with a larger sample size is required to confirm the efficacy of the scale. CLINICAL RELEVANCE STATEMENT: This 12-score CT scale would help clinicians evaluate the resectability of locally advanced thyroid cancer. KEY POINTS: • The researchers built a 12-score CT scale (including recurrent laryngeal nerve, trachea, oesophagus, artery, vein, and soft tissue) to evaluate the resectability of locally advanced thyroid cancer. • This scale has the potential to help clinicians make treatment plans for locally advanced thyroid cancer.

Robotic guidance for percutaneous placement of triangular osteosynthesis in vertically unstable sacrum fractures: a single-center retrospective study.

BACKGROUND: To evaluate the effectiveness and safety of robot-aided percutaneous triangular osteosynthesis combined with close reduction for vertically unstable sacrum fractures (VUSFs). METHODS: The data on 21 patients of the VUSF were retrospectively analyzed from November 2016 to January 2021. According to Denis classification, there were 3 cases in zone I, 11 cases in zone II, and 7 case in zone III. The main perioperative indicators were recorded. The maximal angulation and displacement deviations of the screws were analyzed by comparing the planned trajectory with the actual position. Postoperative X-ray radiographs and CT scans were obtained for evaluating the reduction quality. Functional outcome was scored with Majeed criterion. RESULTS: Fourteen patients of the unilateral VUSF and 7 patients of the bilateral VUSF underwent unilateral and bilateral triangular osteosynthesis with robotic assistance, respectively. No intraoperative neurovascular injuries and postoperative infection occurred. All patients were followed up for at least 12 months. The average operation time of posterior pelvic ring was 111.4 min, with the mean intraoperative bleeding of 110.5 ml. A total of 58 pedicle and iliosacral screws were implanted with robotic assistance. Of those, 52 screws were in the cancellous bone except 4 pedicle and 2 iliosacral screws cutting the cortical bone. The angulation and displacement deviations of the screws were 4.2° ± 2.5° and 1.7 ± 0.9 mm, respectively. The average displacement of the sacral fracture was reduced from 19.7 mm preoperatively to 3.1 mm postoperatively. According to Matta's criterion, the reduction quality was graded as "excellent" in 13 patients and "good" in 8. All sacral fractures healed within 6 months except one fracture with nonunion. The mean Majeed score at the last follow-up was 89.6. CONCLUSIONS: Robot-aided triangular osteosynthesis combined with close reduction provide a safe and reliable option for percutaneous treatment of the fresh VUSF, with a high accuracy of iliosacral and pedicle screw implantation except insertion of iliac screws. Meanwhile, the technique may help to reduce incision-related complications.

Bidirectional crosstalk between therapeutic cancer vaccines and the tumor microenvironment: Beyond tumor antigens.

Immunotherapy has rejuvenated cancer therapy, especially after anti-PD-(L)1 came onto the scene. Among the many therapeutic options, therapeutic cancer vaccines are one of the most essential players. Although great progress has been made in research on tumor antigen vaccines, few phase III trials have shown clinical benefits. One of the reasons lies in obstruction from the tumor microenvironment (TME). Meanwhile, the therapeutic cancer vaccine reshapes the TME in an ambivalent way, leading to immune stimulation or immune escape. In this review, we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME. With respect to vaccine resistance, innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved. Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

Comparative retrospective study of triangular osteosynthesis with and without robotic assistance for unilateral unstable sacral fractures combined with lumbosacral junction injuries.

BACKGROUND: To compare the clinical efficacy of unilateral unstable sacral fractures (USFs) involving the lumbosacral region treated with and without robot-aided triangular osteosynthesis (TOS). METHODS: Patients of the unilateral USF combined with the ipsilateral lumbosacral junction injury (LSJI) treated with TOS were retrospectively analyzed and divided into two groups: the robot group (TOS with robotic assistance) and the conventional group (TOS with open procedure). Screw placement was assessed using the modified Gras criterion. Patients were followed up with routine visits for clinical and radiographic examinations. At the final follow-up, clinical outcomes were recorded and scored using the Majeed scoring system. RESULTS: Eleven patients in the robot group and seventeen patients in the conventional group were recruited into this study. Significant differences in surgical bleeding (P < 0.001) and fluoroscopy time (P = 0.002) were noted between the two groups. Operation time (P = 0.027) and fracture healing time (P = 0.041) was shorter in the robot group. There was no difference in postoperative residual displacement between the two groups (P = 0.971). According to the modified Gras criterion, the percentages of grade I for sacroiliac screws in the two groups were 90.9% (10/11) and 70.6% (12/17), and for pedicle screws were 100% (11/11) and 100% (17/17), respectively. The rate of incision-related complications was 0% (0/11) in the robot group and 11.8% (2/17) in the conventional group. Statistical differences were shown on the Majeed criterion (P = 0.039), with higher scores in the robot group. CONCLUSION: TOS with robotic assistance for the treatment of unilateral USFs combined with ipsilateral LSJIs is safe and feasible, with the advantages of less radiation exposure and fewer incision-related complications.

Radiomics features for assessing tumor-infiltrating lymphocytes correlate with molecular traits of triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have become a promising biomarker for assessing tumor immune microenvironment and predicting immunotherapy response. However, the assessment of TILs relies on invasive pathological slides. METHODS: We retrospectively extracted radiomics features from magnetic resonance imaging (MRI) to develop a radiomic cohort of triple-negative breast cancer (TNBC) (n = 139), among which 116 patients underwent transcriptomic sequencing. This radiomic cohort was randomly divided into the training cohort (n = 98) and validation cohort (n = 41) to develop radiomic signatures to predict the level of TILs through a non-invasive method. Pathologically evaluated TILs in the H&E sections were set as the gold standard. Elastic net and logistic regression were utilized to perform radiomics feature selection and model training, respectively. Transcriptomics was utilized to infer the detailed composition of the tumor microenvironment and to validate the radiomic signatures. RESULTS: We selected three radiomics features to develop a TILs-predicting radiomics model, which performed well in the validation cohort (AUC 0.790, 95% confidence interval (CI) 0.638-0.943). Further investigation with transcriptomics verified that tumors with high TILs predicted by radiomics (Rad-TILs) presented activated immune-related pathways, such as antigen processing and presentation, and immune checkpoints pathways. In addition, a hot immune microenvironment, including upregulated T cell infiltration gene signatures, cytokines, costimulators and major histocompatibility complexes (MHCs), as well as more CD8+ T cells, follicular helper T cells and memory B cells, was found in high Rad-TILs tumors. CONCLUSIONS: Our study demonstrated the feasibility of radiomics model in predicting TILs status and provided a method to make the features interpretable, which will pave the way toward precision medicine for TNBC.

Radiogenomic analysis reveals tumor heterogeneity of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subset of breast cancer with an adverse prognosis and significant tumor heterogeneity. Here, we extract quantitative radiomic features from contrast-enhanced magnetic resonance images to construct a breast cancer radiomic dataset (n = 860) and a TNBC radiogenomic dataset (n = 202). We develop and validate radiomic signatures that can fairly differentiate TNBC from other breast cancer subtypes and distinguish molecular subtypes within TNBC. A radiomic feature that captures peritumoral heterogeneity is determined to be a prognostic factor for recurrence-free survival (p = 0.01) and overall survival (p = 0.004) in TNBC. Combined with the established matching TNBC transcriptomic and metabolomic data, we demonstrate that peritumoral heterogeneity is associated with immune suppression and upregulated fatty acid synthesis in tumor samples. Collectively, this multi-omic dataset serves as a useful public resource to promote precise subtyping of TNBC and helps to understand the biological significance of radiomics.

Therapeutic effects of myricetin on atopic dermatitis in vivo and in vitro.

BACKGROUND: Myricetin (Myr) is a flavonoid compound that exist widely in many natural plants. Myr has been proven to have multiple biological functions, including immunomodulatory and anti-inflammatory effects. PURPOSE: In this study, we investigated the therapeutic effect of Myr on calcipotriol (MC903) induced atopic dermatitis (AD) mouse model and tumor necrosis factor (TNF)-α/interferon (IFN)-γ stimulated human immortal keratinocyte line (HaCaT) in vivo and in vitro. METHODS: MC903 was applied topically to the left ears of mice to establish AD mouse model. After the AD model established successfully, the cream base, dexamethasone (DEX) cream or Myr cream were applied on the lesions of mice for 8 days. Through measuring ear thickness and scoring dermatitis severity, we evaluated the therapeutic effect of Myr, the draining lymph nodes (DLNs) and ears of the mice were collected for mechanistic study. In addition, TNF-α and IFN-γ-activated HaCaT cells were used to investigate the underlying mechanism. RESULTS: Our data demonstrated that Myr alleviated the symptoms of AD by exerting anti-inflammatory and anti-allergic functions in vivo. We found that Myr treatment suppressed ear swelling and IgE level in the serum, reduced the infiltration of mast cells in skin lesions, decreased expressions of thymus and activation regulated chemokine (TARC), IL-4, IFN-γ and thymic stromal lymphopoietin (TSLP) in ear lesions, increased the expressions of filaggrin (FLG). Furthermore, our experimental results demonstrated that Myr down-regulated the mRNA expressions of T-bet and GATA-3 in DLNs. In vitro, Myr treatment decreased MDC and TARC expressions in IFN-γ and TNF-α-induced HaCaT cells by blocking the NF-κB and STAT1 signal pathway. CONCLUSION: The present study is the first to investigate the anti-atopic effects of Myr. Our findings suggested the therapeutic effects of Myr against MC903-induced AD-like skin lesions in mice. Therefore, Myr may be a potential therapeutic agent for AD.

Superconductivity Induced by Site-Selective Arsenic Doping in Mo5Si3.

Arsenic doping in silicides has been much less studied compared with phosphorus. In this study, superconductivity is successfully induced by As doping in Mo5Si3. The superconducting transition temperature (Tc) reaches 7.7 K, which is higher than those in previously known W5Si3-type superconductors. Mo5Si2As is a type-II BCS superconductor with upper and lower critical fields of 6.65 T and 22.4 mT, respectively. In addition, As atoms are found to selectively take the 8h sites in Mo5Si2As. The emergence of superconductivity is possibly due to the shift of Fermi level as a consequence of As doping, as revealed by the specific heat measurements and first-principles calculations. Our work provides not only another example of As doping but also a practical strategy to achieve superconductivity in silicides through Fermi level engineering.

A Multiomics Signature Highlights Alterations Underlying Homologous Recombination Deficiency in Triple-Negative Breast Cancer.

BACKGROUND: Homologous recombination (HR) is a key pathway in DNA double-strand damage repair. HR deficiency (HRD) occurs more commonly in triple-negative breast cancers (TNBCs) than in other breast cancer subtypes. Several clinical trials have demonstrated the value of HRD in stratifying breast cancer patients into distinct groups based on their responses to poly(ADP ribose) polymerase inhibitors and chemotherapy. METHODS: We retrospectively collected TNBC samples to establish a multiomics cohort (n = 343) and explored the biological and phenotypic mechanisms underlying the better prognosis of patients with high HRD scores. Gene set enrichment analysis was conducted to elucidate the underlying pathways in patients with low HRD scores, and a radiomics model was established to predict the HRD score via a noninvasive method. RESULTS: Multivariable Cox analysis revealed the independent prognostic value of a low HRD score (hazard ratio 2.20, 95% confidence interval 1.05-4.59; p = 0.04). Furthermore, amino acid and lipid metabolism pathways were highly enriched in tumors from patients with low HRD scores, which was also demonstrated by differential abundant metabolite analysis. A noninvasive radiomics method was developed to predict the HRD status and it performed well in the independent validation cohort (support vector machine model: area under the curve [AUC] 0.739, sensitivity 0.571, and specificity 0.824; logistic regression model: AUC 0.695, sensitivity 0.571, and specificity 0.882). CONCLUSIONS: We revealed the prognostic value of the HRD score, predicted the HRD status with noninvasive radiomics features, and preliminarily explored druggable targets for TNBC patients with low HRD scores.

Efficacy and Prognosis of Hyperbaric Oxygen as Adjuvant Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Meta-Analysis Study.

Background: Preclinical and clinical evidence suggests that hyperbaric oxygen therapy (HBOT) may benefit newborns. The effectiveness of HBOT for neonatal hypoxic-ischemic encephalopathy (HIE) remains controversial. We conducted a meta-analysis to evaluate the efficacy and prognosis of HBOT in neonates with HIE. Methods: A systematic search of eight databases was performed for available articles published between January 1, 2015, and September 30, 2020, to identify randomized controlled clinical trials (RCTs) on HBOT for neonatal HIE. Methodological quality assessment was performed by applying the simple procedure detailed by the Cochrane collaboration. Afterward, quality assessment and data analysis were performed using Revman 5.3 software. STATA 15 software was used to detect publication bias as well as for sensitivity analysis. Results: A total of 46 clinical RCTs were selected for the study and included 4,199 patients with neonatal HIE. The results indicated that HBOT significantly improved the total efficiency (TEF) of treatment for neonatal HIE patients [odds ratio (OR) = 4.61, 95% confidence interval (CI) (3.70, 5.75), P < 0.00001] and reduced the risk of sequelae (OR = 0.23, 95% CI (0.16, 0.33), P < 0.00001) and the neonatal behavioral neurological assessment (NBNA) scores [mean difference (MD) = 4.51, 95%CI (3.83,5.19, P < 0.00001)]. Conclusion: In light of the effectiveness of HBOT neonatal HIE, this meta-analysis suggested that HBOT can be a potential therapy for the treatment of neonatal HIE. Due to the heterogeneity of studies protocol and patient selection being only from China, more research is needed before this therapy can be widely implemented in the clinic. Protocol Registration: PROSPERO (ID: CRD42020210639). Available online at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020210639.

Idarucizumab reverses dabigatran-induced anticoagulation in treatment of gastric bleeding: A case report.

BACKGROUND: The drug instructions for dabigatran recommend adjusting the dosage to 110 mg twice daily for patients with bleeding risk, and performing at least one renal function test per year for patients with moderate renal impairment. However, owing to chronic insidiously worsening renal insufficiency, dabigatran can still accumulate abnormally, necessitating therapy with idarucizumab to reverse the anticoagulation due to severe erosive gastritis with widespread stomach mucosal bleeding. CASE SUMMARY: A 76-year-old woman with a history of atrial fibrillation who took dabigatran 110 mg twice daily as directed to lessen the chance of stroke, was transported to the hospital with hematemesis and melena. Laboratory findings revealed severe life-threatening, blood-loss-induced anemia with a hemoglobin (Hb) level of 41.0 g/L and marked coagulation abnormalities with thrombin time (TT) > 180 s, most likely caused by dabigatran-induced metabolic disorder. Aggressive acid suppressive, hemostatic, and blood transfusion therapy resulted in the misconception that the bleeding was controlled, with subsequent rebleeding. Idarucizumab was administered in a timely manner to counteract dabigatran's anticoagulant impact, and 12 h later, TT was determined to be 17.4 s, which was within the normal range. Finally, the patient had no active bleeding signs and laboratory findings showed an Hb level of 104 g/L and TT of 17.7 s. CONCLUSION: Renal function, coagulation function, and dabigatran concentration should be regularly monitored in older patients. Proton pump inhibitor and dabigatran coadministration is still controversial in preventing upper gastrointestinal tract bleeding.

Bioinspired Polysaccharide-Derived Zwitterionic Brush-like Copolymer as an Injectable Biolubricant for Arthritis Treatment.

Developing highly efficient and biocompatible biolubricants for arthritis treatment is extraordinarily demanded. Herein, inspired by the efficient lubrication of synovial joints, a paradigm that combines natural polysaccharide (chitosan) with zwitterionic poly[2-(methacryloyloxy) ethyl phosphorylcholine] (PMPC), to design a series of brush-like Chitosan-g-PMPC copolymers with highly efficient biological lubrication and good biocompatibility is presented. The Chitosan-g-PMPC copolymers are prepared via facile one-step graft polymerization in aqueous medium without using any toxic catalysts and organic solvents. The as-prepared Chitosan-g-PMPC copolymers exhibit very low coefficient of friction (µ < 0.01) on Ti6 Al4 V alloy substrate in both pure water and biological fluids. The superior lubrication is attributed primarily to the hydrated feature of PMPC side chains, interface adsorption of copolymer as well as to the hydrodynamic effect. In vivo experiments confirm that Chitosan-g-PMPC can alleviate the swelling symptom of arthritis and protect the bone and cartilage from destruction. Due to their facile preparation, distinctive lubrication properties, and good biocompatibility, Chitosan-g-PMPC copolymers represent a new type of biomimetic lubricants derived from natural biopolymer for promising arthritis treatment and artificial joint lubrication.

The Kocher-Langenbeck approach combined with robot-aided percutaneous anterior column screw fixation for transverse-oriented acetabular fractures: a retrospective study.

OBJECTIVE: Transverse-oriented acetabular fractures (TOAFs), including transverse, transverse with posterior wall and T-shaped fractures, are always challenging for double-column reduction and fixation with minimally invasive method. The purpose of this study is to compare the therapeutic effects of robot-aided percutaneous anterior column screw fixation versus minimally invasive anterior plate fixation for TOAFs based on the Kocher-Langenbeck (K-L) approach. METHODS: Patients suffering TOAFs that were fixed by robot-aided percutaneous anterior column screw fixation or minimally invasive anterior plate fixation associated with posterior fixation via the K-L approach were divided into two groups: group A (screw fixation) and group B (plate fixation). Surgical time, blood loss, incision length for anterior fixation and complications were recorded. Fracture reduction quality was evaluated using criteria described by Matta. Fracture healing was assessed on the series of pelvic radiographs at each follow-up. Functional outcomes were investigated using the modified Postel Merle D'Aubigne score at the final follow-up. RESULTS: Twenty-nine patients with TOAFs, including 12 patients in group A and 17 patients in group B, were evaluated for study eligibility. The mean surgical time of anterior fracture fixation was 18.7 ± 4.6 min in group A and 33.4 ± 5.0 min in group B (P < 0.001). The amount of intraoperative blood loss was 615.6 ± 178.7 ml in group A and 719.3 ± 199.0 ml in group B (P < 0.001). Incision length for anterior fixation was 9.0 ± 1.8 mm in group A and 81.2 ± 7.3 mm in group B (P < 0.001). The complications related to the surgery of anterior column only occurred in group B (lateral femoral cutaneous nerve palsy in 1 patient and groin discomfort in 1 patient). No significant differences in reduction quality, hospital stay, fracture healing time and functional results were noted between the two groups. CONCLUSION: The K-L approach combined with robot-aided anterior column screw fixation is a safe and effective option for TOAFs. Compared with minimally invasive anterior plate fixation, robot-aided screw fixation has obvious advantages on surgical time, blood loss, and invasiveness. The K-L approach combined with minimally invasive anterior plate fixation can also be a reliable alternative for TOAFs, with the similar reduction quality and functional results.

METTL3 modulates m6A modification of CDC25B and promotes head and neck squamous cell carcinoma malignant progression.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation and its methyltransferase METTL3 have been widely reported to be involved in different cancers by regulating RNA metabolism and function. Here, we aimed to explore the biological function and clinical significance of m6A modification and METTL3 in head and neck squamous cell carcinoma (HNSCC). METHODS: The prognostic value of METTL3 expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HNSCC cohort. The biological role and mechanism of METTL3 in HNSCC tumour growth, metastasis and angiogenesis were determined in vitro and in vivo. RESULTS: M6A levels and METTL3 expressions in HNSCC tissues were significantly increased compared with paired adjacent tissues. Meanwhile, METTL3 was an independent risk factor for the prognosis of HNSCC patients. Moreover, METTL3 overexpression promoted HNSCC cell proliferation, migration, invasion, and angiogenesis, while knockdown of METTL3 had an opposite effect in vivo and in vitro. Mechanistically, METTL3 enhanced the m6A modification of CDC25B mRNA, which maintained its stability and upregulated its expression, thereby activating G2/M phase of cell cycle and leading to HNSCC malignant progression. CONCLUSIONS: METTL3 may be a potential prognostic biomarker and therapeutic target for HNSCC.