Osseointegration potential of boron-coated titanium alloy pedicle screw in rabbit spine model.

BACKGROUND: Spinal implants' longevity is crucial, but titanium alloys, while advantageous, lack strong bone integration. This study aimed to achieve better osseointegration rates by utilizing the ability of boron compounds to transform stem cells in the vertebra into osteoblasts. METHOD: Twenty male albino rabbits were divided into control (n = 10) and experimental (n = 10) groups. Control group received titanium alloy pedicle screws, while experimental group received boron-coated titanium alloy screws. Under general anesthesia, screws were inserted into the L6 and L7 lumbar spines. After 16 weeks, all animals were euthanized for histological examination. Vertebra samples underwent decalcification and H&E staining. Microscopic examination assessed osseointegration, necrosis, fibrosis, and vascularization using a triple scoring system by two blinded observers. RESULT: In the boron-coated titanium alloy group, all subjects exhibited osseointegration, with 50% showing focal, 40% moderate, and 10% complete osseointegration. In the titanium alloy group, 90% showed osseointegration (70% focal, 10% moderate, and 10% complete).The differences between the groups were not statistically significant (p = 0.302). Focal necrosis rates were similar between groups, with 50.0% in the titanium alloy and 60.0% in the boron-coated group (p = 0.653).Fibrosis was absent in the titanium alloy group but present in the boron-coated group, albeit with lower rates of focal fibrosis (20.0%). However, the difference was not statistically significant (p = 0.086).Vascularization patterns showed no significant difference between groups. CONCLUSION: Boron-coated titanium alloy pedicle screws provided osseointegration rates comparable to standard titanium screws and exhibited acceptable levels of necrosis and fibrosis. With stronger biomechanical properties, they could be a better alternative to currently used titanium screws.

Factors Affecting Resorption Following Cranioplasty with an Autologous Bone Graft.

AIM: To evaluate the relationship between the surgical techniques, the waiting time for surgery, postoperative distance between the graft-bone margin and the percentage of bone resorption, we analyzed patients who underwent cranioplasty. Cranioplasty is a necessary surgery to preserve brain tissue and provide an appropriate microenvironment. MATERIAL AND METHODS: In this study, patients who underwent autologous bone grafting after decompressive craniectomy by the Neurosurgery Clinic of University of Health Sciences Ankara Training and Research Hospital between 2018 and 2021 were examined. RESULTS: Thirty-nine patients who underwent autologous cranioplasty following decompressive craniectomy were included in the study. The average expected time for cranioplasty surgery following decompressive craniectomy was 16.97±13.478 weeks (min:2 max:62 weeks). The expected time between decompressive craniectomy and cranioplasty surgeries and resorption rates were compared. The resorption rate was above 30% in 7 of 10 patients with 24 weeks or more between craniectomy and cranioplasty, and less than 30% in 17 of 25 patients in surgeries less than 24 weeks (p=0.04). Following cranioplasty surgery, the distance between the graft-bone margin and the resorption rates were also compared. In this analysis, statistically significant differences were detected between the distance between the graft-bone border and the resorption rates. Resorption rates increased in 15 of 19 patients with a postcranioplasty distance of 1 mm or more (p < 0.00001). CONCLUSION: Early cranioplasty surgery is important in order to reduce complications that may occur after craniectomy. In addition, it is important to keep the defect area small in size during craniectomy surgery and to keep the cutting edge thinner when the bone graft is taken, in order to reduce the development of bone graft resorption.

Retrospective Evaluation of Patients with Spontaneous Intracerebral Hematomas

AIM: To investigate the relationship among the modified Rankin scores of patients who had intracerebral hematomas at discharge, demographic characteristics of the patients, and the characteristics of the hematoma. MATERIAL AND METHODS: In this study, patients diagnosed with intracerebral hematoma and treated at the Ministry of Health Ankara Training and Research Hospital Neurosurgery Clinic between January 2010 and December 2020 were examined retrospectively. The age, gender, comorbidity, anticoagulant?antiaggregant use, and Glasgow Coma Scale score of the patients were obtained from hospital records. The modified Rankin scale (mRS) was used to assess patients at discharge. RESULTS: Herein, a total of 114 patients with supratentorial intracerebral hematoma were evaluated. The modified Rankin score ranged from 0 to 6, with a mean score of 3.47 ± 2.26. When the patients were evaluated based on their discharge status, the mortality rate was 33.3% (n=38). Fifty percent of the patients who used anticoagulant?antiaggregant died. High mRS scores were seen more frequently in advanced age. Among the other diseases of the patients, hypertension and the use of anticoagulant? antiaggregant were found to be statistically significant with high mRS scores (p < 0.001). Patients with low Glasgow Coma Scale score at the time of admission had significantly higher mRS scores (p < 0.001). CONCLUSION: Patients with advanced age, hypertension, and anticoagulant?antiaggregant use had a higher mRS score after hematoma formation. Preventable risk factors for spontaneous intraparenchymal hematomas are among the leading causes of disability, and early detection and treatment of underlying diseases are critical for hematoma prevention. Awareness about risk factors should be the priority to improve early diagnosis and reduce treatment disability rates.

Effects of Transcranial Direct Current Stimulation on Motor and Cognitive Dysfunction in an Experimental Traumatic Brain Injury Model.

AIM: To investigate the therapeutic and neuroprotective effects of transcranial direct current stimulation (tDCS) application on the traumatic brain injury (TBI)-induced glutamate and calcium excitotoxicity and loss of motor and cognitive functions. MATERIAL AND METHODS: Forty rats were equally divided in the sham, TBI, tDCS + TBI + tDCS, and TBI + tDCS groups. Mild TBI was induced by dropping a 450-g iron weight from a height of 1 m onto the skull of the rats. The tDCS + TBI + tDCS group was prophylactically administered 1 mA stimulation for 30 min for 7 days starting 5 days before inducing TBI. In the TBI + tDCS group, tDCS (1 mA for 30 min) was administered 2 h after TBI, on days 1 and 2. Cognitive and locomotor functions were assessed using the novel object recognition and open field tests. The calcium, glutamate, and N-methyl-D-aspartate receptor 1 (NMDAR1) levels in the hippocampus were measured using enzyme-linked immunosorbent assay. RESULTS: Although the motor and cognitive functions were substantially reduced in the TBI group when compared with the sham, they improved in the treatment groups (p < 0.05). The calcium, glutamate, and NMDAR1 levels were considerably higher in the TBI group than in the sham (p < 0.001). However, they were considerably lower in the tDCS + TBI + tDCS and TBI + tDCS groups than in the TBI groups (p < 0.05). In particular, the change in the tDCS + TBI + tDCS group was higher than that in the TBI + tDCS group. CONCLUSION: Application of tDCS before the development of TBI improved motor and cognitive dysfunction. It demonstrated a neuroprotective and therapeutic effect by reducing the excitotoxicity via the regulation of calcium and glutamate levels.

COVID-19 Detection From Respiratory Sounds With Hierarchical Spectrogram Transformers.

Monitoring of prevalent airborne diseases such as COVID-19 characteristically involves respiratory assessments. While auscultation is a mainstream method for preliminary screening of disease symptoms, its utility is hampered by the need for dedicated hospital visits. Remote monitoring based on recordings of respiratory sounds on portable devices is a promising alternative, which can assist in early assessment of COVID-19 that primarily affects the lower respiratory tract. In this study, we introduce a novel deep learning approach to distinguish patients with COVID-19 from healthy controls given audio recordings of cough or breathing sounds. The proposed approach leverages a novel hierarchical spectrogram transformer (HST) on spectrogram representations of respiratory sounds. HST embodies self-attention mechanisms over local windows in spectrograms, and window size is progressively grown over model stages to capture local to global context. HST is compared against state-of-the-art conventional and deep-learning baselines. Demonstrations on crowd-sourced multi-national datasets indicate that HST outperforms competing methods, achieving over 90% area under the receiver operating characteristic curve (AUC) in detecting COVID-19 cases.

Mucosa-Associated Lymphoid Tissue Lymphoma With Lymphomeningothelial Lesion of the Dura.

Mucosa-associated lymphoid tissue (MALT) was first described as low-grade lymphoma associated with the stomach mucosa. Although the stomach and ocular adnexa are the most common localizations of MALT lymphoma, it has also been described in many other organs, including the head and neck, lungs, thyroid, breast, bladder, saliva glands, conjunctiva, and tear glands. MALT lymphoma originating from the dura is rare. The case is here presented of an 83-year-old female operated on with an initial diagnosis of acute subdural hematoma. In the histopathological examination, there was seen to be lymphoplasmacytic infiltration of the dura and a lymphomeningothelial lesion. Immunohistochemically, low-grade MALT lymphoma showing B-cell phenotype was considered. This is the first reported case of lymphomeningothelial lesion in MALT lymphoma originating from the dura.

The Comparison of Autologous Bone, Methyl-Methacrylate, Porous Polyethylene, and Titanium Mesh in Cranioplasty.

AIM: To discuss four different materials that are frequently used in cranioplasty, and to reveal their advantages and disadvantages. MATERIAL AND METHODS: We retrospectively reviewed 85 of our cranioplasty surgeries between 2016 and 2019. Reconstruction surgeries were excluded from our study due to craniofacial trauma. RESULTS: Of the materials used in cranioplasty, 33 are autologous bone, 32 are methyl-methacrylate, 12 are porous polyethylene, and 8 are titanium mesh. Complications developed in 16 patients. Of these, 10 are infection, 3 are flap collapse, 2 are wound healing disorders, and 1 is reactive effusion complications due to the used material. The highest complication rate was 21.9% in cranioplasty with methyl-methacrylate. No major complications were observed in cranioplasty with titanium mesh. CONCLUSION: Cranioplasty, which are among the surgeries with high complications in neurosurgery, maintain their importance today. As technology is developed and cost problems are resolved, cranioplasty takes its place among the safer and standard neurosurgical operations.

Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells.

Clofarabine, an FDA approved purine analog, is used in the treatment of relapsed or refractory acute lymphoblastic leukemia. Clofarabine acts by inhibiting DNA synthesis. We demonstrated that clofarabine may have a novel function though inhibiting CD99, a transmembrane protein highly expressed on Ewing Sarcoma (ES) cells. CD99 is a validated target in ES whose inhibition may lead to a high therapeutic index for patients. Here we present additional data to support the hypothesis that clofarabine acts on CD99 and regulates key signaling pathways in ES. Cellular thermal shift assay indicated a direct interaction between clofarabine and CD99 in ES cell lysates. Clofarabine induced ES cell death does not require clofarabine's conversion to its active form by deoxycytidine kinase. A phosphokinase array screen with clofarabine and a CD99 blocking antibody identified alterations in signaling pathways. CD99 inhibition with clofarabine in ES cells caused rapid and sustained phosphorylation of ERK, MSK, and CREB. However, activation of this pathway did not correlate with clofarabine induced ES cell death. In summary, we demonstrated that clofarabine may activate ERK, MSK, and CREB phosphorylation through CD99 within minutes, however this paradoxical activation and subsequent ES cell death requires additional investigation.

Integrating Eye Tracking and Speech Recognition Accurately Annotates MR Brain Images for Deep Learning: Proof of Principle.

PURPOSE: To generate and assess an algorithm combining eye tracking and speech recognition to extract brain lesion location labels automatically for deep learning (DL). MATERIALS AND METHODS: In this retrospective study, 700 two-dimensional brain tumor MRI scans from the Brain Tumor Segmentation database were clinically interpreted. For each image, a single radiologist dictated a standard phrase describing the lesion into a microphone, simulating clinical interpretation. Eye-tracking data were recorded simultaneously. Using speech recognition, gaze points corresponding to each lesion were obtained. Lesion locations were used to train a keypoint detection convolutional neural network to find new lesions. A network was trained to localize lesions for an independent test set of 85 images. The statistical measure to evaluate our method was percent accuracy. RESULTS: Eye tracking with speech recognition was 92% accurate in labeling lesion locations from the training dataset, thereby demonstrating that fully simulated interpretation can yield reliable tumor location labels. These labels became those that were used to train the DL network. The detection network trained on these labels predicted lesion location of a separate testing set with 85% accuracy. CONCLUSION: The DL network was able to locate brain tumors on the basis of training data that were labeled automatically from simulated clinical image interpretation.© RSNA, 2020.

Proceedings from the First Global Artificial Intelligence in Gastroenterology and Endoscopy Summit.

BACKGROUND AND AIMS: Artificial intelligence (AI), specifically deep learning, offers the potential to enhance the field of GI endoscopy in areas ranging from lesion detection and classification to quality metrics and documentation. Progress in this field will be measured by whether AI implementation can lead to improved patient outcomes and more efficient clinical workflow for GI endoscopists. The aims of this article are to report the findings of a multidisciplinary group of experts focusing on issues in AI research and applications related to gastroenterology and endoscopy, to review the current status of the field, and to produce recommendations for investigators developing and studying new AI technologies for gastroenterology. METHODS: A multidisciplinary meeting was held on September 28, 2019, bringing together academic, industry, and regulatory experts in diverse fields including gastroenterology, computer and imaging sciences, machine learning, computer vision, U.S. Food and Drug Administration, and the National Institutes of Health. Recent and ongoing studies in gastroenterology and current technology in AI were presented and discussed, key gaps in knowledge were identified, and recommendations were made for research that would have the highest impact in making advances and implementation in the field of AI to gastroenterology. RESULTS: There was a consensus that AI will transform the field of gastroenterology, particularly endoscopy and image interpretation. Powered by advanced machine learning algorithms, the use of computer vision in endoscopy has the potential to result in better prediction and treatment outcomes for patients with gastroenterology disorders and cancer. Large libraries of endoscopic images, "EndoNet," will be important to facilitate development and application of AI systems. The regulatory environment for implementation of AI systems is evolving, but common outcomes such as colon polyp detection have been highlighted as potential clinical trial endpoints. Other threshold outcomes will be important, as well as clarity on iterative improvement of clinical systems. CONCLUSIONS: Gastroenterology is a prime candidate for early adoption of AI. AI is rapidly moving from an experimental phase to a clinical implementation phase in gastroenterology. It is anticipated that the implementation of AI in gastroenterology over the next decade will have a significant and positive impact on patient care and clinical workflows. Ongoing collaboration among gastroenterologists, industry experts, and regulatory agencies will be important to ensure that progress is rapid and clinically meaningful. However, several constraints and areas will benefit from further exploration, including potential clinical applications, implementation, structure and governance, role of gastroenterologists, and potential impact of AI in gastroenterology.

Are Current Technical Exclusion Criteria for Clinical Trials of Magnetic Resonance-Guided High-Intensity Focused Ultrasound Too Restrictive?: Early Experiences at a Pediatric Hospital.

Certain technical criteria must be met to ensure the treatment safety of magnetic resonance-guided high-intensity focused ultrasound. We retrospectively reviewed how our enrollment criteria were applied from 2014 to 2017 in a clinical trial of magnetic resonance-guided high-intensity focused ultrasound ablation of recurrent malignant and locally aggressive benign solid tumors. Among the 36 screened patients between 2014 and 2017, more than one-third were excluded for technical exclusion criteria such as the anatomic location and proximity to prosthetics. Overall, patients were difficult to accrue for this trial, given the incidence of these tumors. To increase potential accrual, screening exclusion criteria could be more generalized and centered on the ability to achieve an acceptable treatment safety margin, rather than specifically excluding on the basis of general anatomic areas.

The Effect of Alpha Lipoic Acid on Cerebrospinal Fluid Biochemistry and Brain Edema After Experimental Traumatic Brain Injury.

AIM: To investigate the effect of alpha lipoic acid on cerebrospinal fluid (CSF) osmolarity and brain tissue water ratio in a rabbit model of traumatic brain injury. MATERIAL AND METHODS: Using a previously established model of traumatic brain injury using liquid nitrogen, 36 New Zealand rabbits were randomized into six groups (three treatment groups, a no trauma/no treatment group, a trauma/no treatment group, and a no trauma/treatment group). The treatment groups were administered intravenous alpha lipoic acid at different times of the experiment. Cerebrospinal fluid was obtained 96 hours after injury/treatment via cisterna magna puncture; glucose, blood urea nitrogen, and sodium levels were measured and osmolarity was calculated. Brain tissue water ratio was determined using wet and dry brain weights. The therapeutic effect of alpha lipoic acid was evaluated by comparing cerebrospinal fluid osmolarity and brain tissue water ratio between study groups. RESULTS: Based on cerebrospinal fluid osmolarity values, alpha lipoic acid treatment effectiveness was greatest in the group that received 3 doses after trauma. CONCLUSION: Alpha lipoic acid is effictive in the treatment of brain edema after experimental traumatic brain injury.

Development of an Ewing sarcoma cell line with resistance to EWS­FLI1 inhibitor YK­4­279.

Despite Ewing sarcoma (ES) being the second most common pediatric malignancy of bone and soft tissue, few novel therapeutic approaches have been introduced over the past few decades. ES contains a pathognomonic chromosomal translocation that leads to a fusion protein between EWSR1 and an ets family member, most often FLI1. EWS­FLI1 is the most common type of fusion protein and is a well­vetted therapeutic target. A small molecule inhibitor of EWS­FLI1, YK­4­279 (YK) was developed with the intention to serve as a targeted therapy option for patients with ES. The present study investigated resistance mechanisms by developing an ES cell line specifically resistant to YK. The ES cell line A4573 was treated with YK to create resistant cells by long term continuous exposure. The results revealed that resistance in A4573 was robust and sustainable, with a >27­fold increase in IC50 lasting up to 16 weeks in the absence of the compound. Resistant ES cells were still sensitive to standard of care drugs, including doxorubicin, vincristine and etoposide, which may be valuable in future combination treatments in the clinic. Resistant ES cells revealed an increased expression of CD99. RNA sequencing and qPCR validation of resistant ES cells confirmed an increased expression of ANO1, BRSK2 and IGSF21, and a reduced expression of COL24A1, PRSS23 and RAB38 genes. A functional association between these genes and mechanism of resistance remains to be investigated. The present study created a cell line to investigate YK resistance.

Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n = 10) and age- and sex-matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource.

Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin.

PURPOSE: To determine whether burn time per tumor volume (BPV) (min/mL), where burn time is the total time during which radiofrequency (RF) energy is being applied, is correlated with hepatocellular carcinoma (HCC) treatment outcomes using RF ablation and lyso-thermosensitive liposomal doxorubicin (LTLD). MATERIALS AND METHODS: The HEAT study was a double-blind, randomized controlled phase III trial of RF ablation only versus RF ablation + LTLD in patients with HCCs 3-7 cm in diameter. Effect of BPV on progression-free survival and overall survival (OS) was analyzed. RESULTS: BPV demonstrated statistically significant differences between study groups for OS (P = .038, hazard ratio [HR] = 0.85), but not for progression-free survival (P = .389, HR = 1.059). In a separate analysis, treatment groups were independently analyzed to determine the effect of BPV within each individual group. OS improved as BPV increased for patients receiving RF ablation + LTLD (P = .017, HR = 0.836, confidence interval [0.722, 0.968]). This same association was not observed in patients receiving RF ablation only (P = .57, HR = 0.99). CONCLUSIONS: BPV may be a useful metric for RF ablation + LTLD combination therapy for solitary HCC. The analysis suggested that the burn time for the tumor needs to be adjusted depending on the tumor volume. Because this is a post hoc study, the results are only suggestive and need to be confirmed with prospective studies.

A collaborative computer aided diagnosis (C-CAD) system with eye-tracking, sparse attentional model, and deep learning.

Computer aided diagnosis (CAD) tools help radiologists to reduce diagnostic errors such as missing tumors and misdiagnosis. Vision researchers have been analyzing behaviors of radiologists during screening to understand how and why they miss tumors or misdiagnose. In this regard, eye-trackers have been instrumental in understanding visual search processes of radiologists. However, most relevant studies in this aspect are not compatible with realistic radiology reading rooms. In this study, we aim to develop a paradigm shifting CAD system, called collaborative CAD (C-CAD), that unifies CAD and eye-tracking systems in realistic radiology room settings. We first developed an eye-tracking interface providing radiologists with a real radiology reading room experience. Second, we propose a novel algorithm that unifies eye-tracking data and a CAD system. Specifically, we present a new graph based clustering and sparsification algorithm to transform eye-tracking data (gaze) into a graph model to interpret gaze patterns quantitatively and qualitatively. The proposed C-CAD collaborates with radiologists via eye-tracking technology and helps them to improve their diagnostic decisions. The C-CAD uses radiologists' search efficiency by processing their gaze patterns. Furthermore, the C-CAD incorporates a deep learning algorithm in a newly designed multi-task learning platform to segment and diagnose suspicious areas simultaneously. The proposed C-CAD system has been tested in a lung cancer screening experiment with multiple radiologists, reading low dose chest CTs. Promising results support the efficiency, accuracy and applicability of the proposed C-CAD system in a real radiology room setting. We have also shown that our framework is generalizable to more complex applications such as prostate cancer screening with multi-parametric magnetic resonance imaging (mp-MRI).

Early synergistic interactions between the HPV16­E7 oncoprotein and 17ß-oestradiol for repressing the expression of Granzyme B in a cervical cancer model.

Although high-risk human papillomavirus (HR­HPV) infection has a prominent role in the aetiology of cervical cancer (CC), sex steroid hormones may also be involved in this process; however, the cooperation between oestrogen and HR­HPV in the early stages of cervical carcinogenesis is poorly understood. Since 17ß-oestradiol (E2) and the HPV type 16­E7 oncoprotein induce CC in transgenic mice, a microarray analysis was performed in the present study to generate global gene expression profiles from 2­month­old FVB (non­transgenic) and K14E7 (transgenic) mice who were left untreated or were treated for 1 month with E2. Upregulation of cancer-related genes that have not been previously reported in the context of CC, including glycerophosphodiester phosphodiesterase domain containing 3, interleukin 1 receptor type II, natriuretic peptide type C, MGAT4 family member C, lecithin-retinol acyltransferase (phosphatidylcholine-retinol-O-acyltransferase) and glucoside xylosyltransferase 2, was observed. Notably, upregulation of the serine (or cysteine) peptidase inhibitor clade B member 9 gene and downregulation of the Granzyme gene family were observed; the repression of the Granzyme B pathway may be a novel mechanism of immune evasion by cancer cells. The present results provide the basis for further studies on early biomarkers of CC risk and synergistic interactions between HR­HPV and oestrogen.

Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99.

Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that predominantly affects children and adolescents. CD99 is a cell surface protein that is highly expressed on ES cells and is required to maintain their malignancy. We screened small molecule libraries for binding to extracellular domain of recombinant CD99 and subsequent inhibition of ES cell growth. We identified two structurally similar FDA-approved compounds, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES vs. 28 non-ES cell lines. Both drugs inhibited CD99 dimerization and its interaction with downstream signaling components. A membrane-impermeable analog of clofarabine showed similar cytotoxicity in culture, suggesting that it can function through inhibiting CD99 independent of DNA metabolism. Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting growth of three different ES xenografts. Our findings provide a novel molecular mechanism for clofarabine that involves direct binding to a cell surface receptor CD99 and inhibiting its biological activities.

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system.

PURPOSE: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. METHODS AND MATERIALS: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. RESULTS: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. CONCLUSION: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system.