A comparative evaluation of the efficiency of warm local anesthetic solution delivered on precooled injection sites with the conventional local anesthetic technique in 7-9-year-old children: A randomized split-mouth cross-over trial.

BACKGROUND: Both precooling the site and injecting a warm anesthetic solution have proven to be efficient in reducing pain individually. However, there is insufficient data on evaluating the efficiency of precooling the site of injection along with the simultaneous administration of a warm local anesthetic solution on the same site in a single patient. AIM: The aim of this study was to evaluate and compare the efficacy, pain perception, hemodynamic changes, and adverse effects of a warm local anesthetic solution injected on precooled injection sites using 2% lignocaine with the conventional local anesthetic technique during inferior alveolar nerve block in 7-9-year-old children. METHODS: A split-mouth, double-blinded, randomized clinical trial was conducted on 70 children who received 2% lignocaine with either technique A or B during the first or second appointment of the treatment procedure. The pain perception, anesthetic efficacy, pulse rate, oxygen saturation levels, and adverse events were evaluated. RESULTS: Pain during injection and treatment after administration of the warm local anesthesia (LA) technique was less as compared to the conventional block technique. Anesthetic success was observed with a faster onset of action (212.57 ± 32.51 s) and shorter duration of LA (165.16 ± 33.09 min) in the warm local technique as compared to the conventional technique. No significant differences were found with regard to heart rate and oxygen saturation levels between the two techniques. Administrating warm LA solutions at precooled injection sites revealed fewer adverse events. CONCLUSION: Injecting warm LA solution on precooled injection sites causes less discomfort and anxiety in children, which makes it more suitable for the child as well as the pediatric dentist.

Comprehensive Review of Inner Ear Anatomy on Photon Counting CT.

The inner ear contains many fissures and canals which can mimic pathology. Photon counting CT allows greater spatial and contrast resolution of these structures over traditional energy integrating CT detectors. Small channels containing nerves, arteries, and normal anatomy such as the cochlear cleft, cochlear and vestibular aqueducts are commonly encountered on temporal bone imaging. The improved visualization of these structures poses challenges for radiologists who are new photon counting CT. This manuscript updates the existing temporal bone anatomy literature with a detailed anatomical review of the inner ear and major nerves frequently encountered when reviewing temporal bone imaging.ABBREVIATIONS: EID = energy-integrating detector; PCT = photon-counting computed tomography, CPA = cerebellopontine angle; IAC = internal auditory canal.

Comprehensive Review of External and Middle Ear Anatomy on Photon Counting CT.

Photon counting CT allows for improved spatial and contrast resolution as compared to traditional energy integrating detector CT. Photon counting CT offers markedly improved visualization of previously described structures, as well as those that were previously beyond the resolution of imaging. Although the anatomical details of the external ear and middle ear structures have been described previously, the rich detail of these structures has not been comprehensively reviewed in the radiology literature. The microarchitecture of the middle ear ossicles and bony protuberances are particularly well visualized on photon counting CT. This manuscript updates the existing literature with a detailed anatomical review of external ear and the middle ear on temporal bone CT.ABBREVIATIONS: EID, energy-integrating detector; PCT, photon-counting computed tomography.

Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo.

While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for its attachment and entry into splenic B cells. Single-cell RNA sequencing analysis of the transduced cells demonstrated that different pseudotypes transduce distinct B cell subpopulations characterized by specific B cell receptor (BCR) genotypes. Functional analysis of the BCRs of the transduced cells demonstrated that BCRs specific to the pseudotyping envelope proteins mediate viral entry, enabling the vectors to selectively transduce the B cell populations that are capable of producing antibodies specific to their envelope proteins. Lentiviral vector entry via the BCR activated the transduced B cells and induced proliferation and differentiation into mature effectors, such as memory B and plasma cells. BCR-mediated viral entry into clonally specific B cell subpopulations raises new concepts for understanding the biodistribution of transgene expression after systemic administration of lentiviral vectors and offers new opportunities for BCR-targeted gene delivery by pseudotyped lentiviral vectors.

Small molecule inhibition of RNA binding proteins in haematologic cancer.

In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

Imaging 3.0: A scoping review.

We aim to provide a comprehensive summary of the current body of literature concerning the Imaging 3.0 initiative and its implications for patient care within the field of radiology. We offer a thorough analysis of the literature pertaining to the Imaging 3.0 initiative, emphasizing the practical application of the five pillars of the program, their cost-effectiveness, and their benefits in patient management. By doing so, we hope to illustrate the impact the Imaging 3.0 Initiative can have on the future of radiology and patient care.

T2-weighted Imaging Hyperintensity and Transcranial Motor-evoked Potentials During Cervical Spine Surgery: Effects of Sevoflurane in 150 Consecutive Cases.

BACKGROUND: There is debate on the impact of inhalational esthetic agents on transcranial motor evoked potentials (TcMEPs) during intraoperative neuromonitoring. Current guidelines advise their avoidance, which contrasts with common clinical practice. METHODS: This retrospective cohort study of 150 consecutive cervical spine surgeries at a single institution compared stimulation voltages and TcMEP amplitudes in patients who did and did not receive sevoflurane as part of a balanced anesthetic technique. Patients were divided into 3 groups stratified by the presence or absence of increased signal intensity within the cervical spinal cord on T2-weighted magnetic resonance imaging (indicative or myelopathy/spinal cord injury [SCI]) and sevoflurane use. RESULTS: Patients with no magnetic resonance imaging evidence of myelopathy/SCI that received sevoflurane (n=80) had the lowest stimulation voltages and largest TcMEP amplitude responses in the lower extremities compared with those with no magnetic resonance imaging evidence of myelopathy/SCI (n=30). In patients with evidence of myelopathy/SCI who did not receive sevoflurane (n=19), lower extremity TcMEP amplitudes were similar to patients with a myelopathy/SCI that received sevoflurane. Six of these 19 patients had initial low-dose sevoflurane discontinued because of concerns of low/absent baseline TcMEP amplitudes. CONCLUSIONS: Balanced anesthesia with 0.5 MAC sevoflurane in patients with and without radiological evidence of myelopathy/SCI allows reliable TcMEP monitoring. However, in communication with surgical and neuromonitoring teams, it may be advisable in a subset of patients to avoid or discontinue sevoflurane in favor of a propofol/opioid-based anesthetic to ensure adequate and reproducible TcMEPs.

Targeting IGF2BP3 enhances antileukemic effects of menin-MLL inhibition in MLL-AF4 leukemia.

ABSTRACT: RNA-binding proteins (RBPs) are emerging as a novel class of therapeutic targets in cancer, including in leukemia, given their important role in posttranscriptional gene regulation, and have the unexplored potential to be combined with existing therapies. The RBP insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3) has been found to be a critical regulator of MLL-AF4 leukemogenesis and represents a promising therapeutic target. Here, we study the combined effects of targeting IGF2BP3 and menin-MLL interaction in MLL-AF4-driven leukemia in vitro and in vivo, using genetic inhibition with CRISPR-Cas9-mediated deletion of Igf2bp3 and pharmacologic inhibition of the menin-MLL interaction with multiple commercially available inhibitors. Depletion of Igf2bp3 sensitized MLL-AF4 leukemia to the effects of menin-MLL inhibition on cell growth and leukemic initiating cells in vitro. Mechanistically, we found that both Igf2bp3 depletion and menin-MLL inhibition led to increased differentiation in vitro and in vivo, seen in functional readouts and by gene expression analyses. IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with small molecule MI-503 alone and showed enhanced antileukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4-mediated leukemogenesis and a potent therapeutic target, providing a paradigm for targeting leukemia at both the transcriptional and posttranscriptional level.

Newly Recognized Genetic Tumor Syndromes of the CNS in the 5th WHO Classification: Imaging Overview with Genetic Updates.

The nervous system is commonly involved in a wide range of genetic tumor-predisposition syndromes. The classification of genetic tumor syndromes has evolved during the past years; however, it has now become clear that these syndromes can be categorized into a relatively small number of major mechanisms, which form the basis of the new 5th edition of the World Health Organization book (beta online version) on genetic tumor syndromes. For the first time, the World Health Organization has also included a separate chapter on genetic tumor syndromes in the latest edition of all the multisystem tumor series, including the 5th edition of CNS tumors. Our understanding of these syndromes has evolved rapidly since the previous edition (4th edition, 2016) with recognition of 8 new syndromes, including the following: Elongator protein complex-medulloblastoma syndrome, BRCA1-associated protein 1 tumor-predisposition syndrome, DICER1 syndrome, familial paraganglioma syndrome, melanoma-astrocytoma syndrome, Carney complex, Fanconi anemia, and familial retinoblastoma. This review provides a description of these new CNS tumor syndromes with a focus on imaging and genetic characteristics.

A quantitative evaluation of the effects of potassium iodide on the clinical properties of silver diamine fluoride.

Silver diamine fluoride (SDF), an effective topical fluoride agent for arresting caries, has a reputation for staining the teeth. Potassium iodide (KI) has been reported to minimize such staining, but doubts remain over its long-term efficacy and potential adverse influence on the effectiveness of SDF. This in vitro study used quantitative evaluation of color changes and the silver and fluoride release of treated tooth specimens to determine the effect of KI on the staining and caries-arresting properties of SDF. Twenty-one noncarious premolars were sectioned buccolingually to create 42 tooth specimens that were divided into 3 groups for color comparison and ion release measurements. The specimens in the experimental group were treated with a combined SDF + KI product (n = 16), the specimens in the positive control group were treated with SDF (n = 16), and the specimens in the negative control group were untreated (n = 10). Digital color analysis was performed weekly for a month according to the CIE L*a*b* color system of the International Commission on Illumination. Atomic spectrophotometry and ion-selective electrodes were used to measure the quantity of fluoride and silver ions released after 24 and 48 hours. The data from the color measurements were analyzed with the Friedman and Fisher tests, while the data from the ion release measurements were analyzed with the Mann-Whitney U and Wilcoxon signed rank tests. The analysis revealed that KI reduced the dentinal staining caused by SDF, but its effectiveness decreased over time as evidenced by the significantly deteriorating perceptual lightness (L*) values of SDF + KI-treated tooth specimens. The SDF + KI-treated specimens released significantly less silver and fluoride ions than the SDF-treated specimens. Because KI lost its stain-reducing property over time and reduced the effectiveness of SDF, a better "antidote" to SDF staining is needed.

When a glimpse is enough: Partial mimicry of jumping spiders by insects.

Many flies and moths mimic the frontal appearance of jumping spiders. This type of mimicry, which we term as partial mimicry, can be distinguished from Batesian mimicry since the mimic has spider resembling patterns only in certain parts of the body, and not the entire body. The presence of spider-like patterns is obvious only at certain angles suggesting that the mimic is frequently targeted by its predators from particular angles. We tested this hypothesis using Deep Convolutional Neural Networks (DCNNs). First, we trained the network on images of forward facing jumping spiders, where features such as the large principal eyes, small lateral eyes and outstretched legs were evident. Then we tested the classifier on images of jumping spider mimicking flies and moths. A probability value according to the likelihood of the image being a jumping spider or not was assigned by the classifier. We show that the classifier was more likely to misidentify mimicking flies and moths as jumping spiders, but that this probability varied according to the species tested. We further tested it on images of flies from different angles and by taking into consideration the visual acuity of potential predators. Our results suggest that neural networks can be efficient tools for testing evolutionary hypotheses, and that partial mimicry may be a result of the effect of the signaling angle and orientation of the mimics in combination with the likelihood that predators may depend on cognitive shortcuts to identify insects as prey. Further experiments incorporating the properties of the visual system of predators (such as vision in ultraviolet) would result in a better understanding of the evolution of partial mimicry.

RNA binding protein IGF2BP1 synergizes with ETV6-RUNX1 to drive oncogenic signaling in B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy, with ETV6::RUNX1 being the most prevalent translocation whose exact pathogenesis remains unclear. IGF2BP1 (Insulin-like Growth Factor 2 Binding Protein 1) is an oncofetal RNA binding protein seen to be specifically overexpressed in ETV6::RUNX1 positive B-ALL. In this study, we have studied the mechanistic role of IGF2BP1 in leukemogenesis and its synergism with the ETV6::RUNX1 fusion protein. METHODS: Gene expression was analyzed from patient bone marrow RNA using Real Time RT-qPCR. Knockout cell lines were created using CRISPR-Cas9 based lentiviral vectors. RNA-Seq and RNA Immunoprecipitation sequencing (RIP-Seq) after IGF2BP1 pulldown were performed using the Illumina platform. Mouse experiments were done by retroviral overexpression of donor HSCs followed by lethal irradiation of recipients using a bone marrow transplant model. RESULTS: We observed specific overexpression of IGF2BP1 in ETV6::RUNX1 positive patients in an Indian cohort of pediatric ALL (n=167) with a positive correlation with prednisolone resistance. IGF2BP1 expression was essential for tumor cell survival in multiple ETV6::RUNX1 positive B-ALL cell lines. Integrated analysis of transcriptome sequencing after IGF2BP1 knockout and RIP-Seq after IGF2BP1 pulldown in Reh cell line revealed that IGF2BP1 targets encompass multiple pro-oncogenic signalling pathways including TNFα/NFκB and PI3K-Akt pathways. These pathways were also dysregulated in primary ETV6::RUNX1 positive B-ALL patient samples from our center as well as in public B-ALL patient datasets. IGF2BP1 showed binding and stabilization of the ETV6::RUNX1 fusion transcript itself. This positive feedback loop led to constitutive dysregulation of several oncogenic pathways. Enforced co-expression of ETV6::RUNX1 and IGF2BP1 in mouse bone marrow resulted in marrow hypercellularity which was characterized by multi-lineage progenitor expansion and strong Ki67 positivity. This pre-leukemic phenotype confirmed their synergism in-vivo. Clonal expansion of cells overexpressing both ETV6::RUNX1 and IGF2BP1 was clearly observed. These mice also developed splenomegaly indicating extramedullary hematopoiesis. CONCLUSION: Our data suggest a combined impact of the ETV6::RUNX1 fusion protein and RNA binding protein, IGF2BP1 in activating multiple oncogenic pathways in B-ALL which makes IGF2BP1 and these pathways as attractive therapeutic targets and biomarkers.

IGF2BP3 as a Prognostic Biomarker in Well-Differentiated/Dedifferentiated Liposarcoma.

BACKGROUND: Although IGF2BP3 has been implicated in tumorigenesis and poor outcomes in multiple cancers, its role in soft-tissue sarcoma (STS) remains unknown. Preliminary data have suggested an association with IGF2BP3 expression among patients with well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a disease where molecular risk stratification is lacking. METHODS: We examined the survival associations of IGF2BP3 via univariate and multivariate Cox regression in three unique datasets: (1) the Cancer Genome Atlas (TCGA), (2) an in-house gene microarray, and (3) an in-house tissue microarray (TMA). A fourth dataset, representing an independent in-house TMA, was used for validation. RESULTS: Within the TCGA dataset, IGF2BP3 expression was a poor prognostic factor uniquely in DD LPS (OS 1.6 vs. 5.0 years, p = 0.009). Within the microarray dataset, IGF2BP3 expression in WD/DD LPS was associated with worse survival (OS 7.7 vs. 21.5 years, p = 0.02). IGF2BP3 protein expression also portended worse survival in WD/DD LPS (OS 3.7 vs. 13.8 years, p < 0.001), which was confirmed in our validation cohort (OS 2.7 vs. 14.9 years, p < 0.001). In the multivariate model, IGF2BP3 was an independent risk factor for OS, (HR 2.55, p = 0.034). CONCLUSION: IGF2BP3 is highly expressed in a subset of WD/DD LPS. Across independent datasets, IGF2BP3 is also a biomarker of disease progression and worse survival.

miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.

Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic.

Visual antipredator effects of web flexing in an orb web spider, with special reference to web decorations.

Some visual antipredator strategies involve the rapid movement of highly contrasting body patterns to frighten or confuse the predator. Bright body colouration, however, can also be detected by potential predators and used as a cue. Among spiders, Argiope spp. are usually brightly coloured but they are not a common item in the diet of araneophagic wasps. When disturbed, Argiope executes a web-flexing behaviour in which they move rapidly and may be perceived as if they move backwards and towards an observer in front of the web. We studied the mechanisms underlying web-flexing behaviour as a defensive strategy. Using multispectral images and high-speed videos with deep-learning-based tracking techniques, we evaluated body colouration, body pattern, and spider kinematics from the perspective of a potential wasp predator. We show that the spider's abdomen is conspicuous, with a disruptive colouration pattern. We found that the body outline of spiders with web decorations was harder to detect when compared to spiders without decorations. The abdomen was also the body part that moved fastest, and its motion was composed mainly of translational (vertical) vectors in the potential predator's optical flow. In addition, with high contrast colouration, the spider's movement might be perceived as a sudden change in body size (looming effect) as perceived by the predator. These effects alongside the other visual cues may confuse potential wasp predators by breaking the spider body outline and affecting the wasp's flight manoeuvre, thereby deterring the wasp from executing the final attack.

Distinct oncogenic phenotypes in hematopoietic specific deletions of Trp53.

Loss of function in the tumor suppressor gene TP53 is the most common alteration seen in human cancer. In mice, P53 deletion in all cells leads predominantly to the development of T-cell lymphomas, followed by B-cell lymphomas, sarcomas and teratomas. In order to dissect the role of P53 in the hematopoietic system, we generated and analyzed two different mouse models deficient for P53. A pan-hematopoietic P53 deletion mouse was created using Vav1-Cre based deletion; and a B-cell-specific deletion mouse was created using a CD19-Cre based deletion. The Vav1-P53CKO mice predominantly developed T-cell malignancies in younger mice, and myeloid malignancies in older mice. In T-cell malignancies, there was accelerated thymic cell maturation with overexpression of Notch1 and its downstream effectors. CD19-P53CKO mice developed marginal zone expansion in the spleen, followed by marginal zone lymphoma, some of which progressed to diffuse large B-cell lymphomas. Interestingly, marginal zone and diffuse large B-cell lymphomas had a unique gene expression signature characterized by activation of the PI3K pathway, compared with wild type marginal zone or follicular cells of the spleen. This study demonstrates lineage specific P53 deletion leading to distinct phenotypes secondary to unique gene expression programs set in motion.

Can Anterior Osteophyte Fractures Be Distinguished From Fracture Mimics in the Subaxial Cervical Spine? A Retrospective Analysis Evaluating Reported Fractures With Clinical Management Correlation.

OBJECTIVE: This study aimed to retrospectively distinguish true- from false-positive fractures of anterior subaxial cervical osteophytes, which were reported on noncontrast computed tomography reports, and to correlate the imaging findings with patient symptoms and analyze the downstream impact on management of both true and false positive fractures. METHODS: A total of 127 patients had computed tomography reports of anterior osteophyte fractures. Radiology reports and imaging studies were evaluated to distinguish true fractures from fracture mimics. We analyzed imaging features including rigid spine (RS), prevertebral soft tissue swelling (PVSTS), and instability. We categorized symptoms and examination findings into 3 groups (0, asymptomatic; 1, neck pain; 2, neurological symptoms). Management was categorized into 3 groups (0, no treatment; 1, external bracing; 2, surgery). Associations between imaging features, fracture classification, clinical symptoms, magnetic resonance imaging utilization, and management were calculated using χ2 with Cramer V test to determine effect size. RESULTS: Eighty patients had false-positive fractures, and 47 were true positive. There were significant associations between magnetic resonance imaging utilization and fracture classification (P ≤ 0.001), PVSTS (P ≤ 0.005), patient symptoms (P ≤ 0.001), and patient management (P ≤ 0.001). There were significant associations between patient management and fracture classification (P ≤ 0.001), patient symptoms (P ≤ 0.001), PVSTS (P ≤ 0.001), imaging findings of instability (P ≤ 0.001), and RS (P ≤ 0.021). There were significant associations between fracture classification and patient symptoms (P ≤ 0.045), and RS (P ≤ 0.006). CONCLUSIONS: Subaxial isolated anterior osteophyte fractures fell into 3 major categories. By our methodology, if a suspected fracture was determined to be a fracture mimic in an asymptomatic patient, it was unlikely to be clinically significant. Isolated anterior osteophyte fractures without neurological symptoms or more concerning imaging findings can be treated conservatively. Finally, fractures that demonstrate indirect signs of instability or are associated with RS are more associated with surgical management.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

The Role of Imaging in Mandibular Reconstruction with Microvascular Surgery.

Imaging plays a critical role in the diagnosis, staging, and management of segmental mandibular defects. Imaging allows mandibular defects to be classified which aids in microvascular free flap reconstruction. This review serves to complement the surgeon's clinical experience with image-based examples of mandibular pathology, defect classification systems, reconstruction options, treatment complications, and Virtual Surgical Planning.