Construing the function of N-terminal domain of D29 mycobacteriophage LysA endolysin in phage lytic efficiency and proliferation.

Endolysins produced by bacteriophages hydrolyze host cell wall peptidoglycan to release newly assembled virions. D29 mycobacteriophage specifically infects mycobacteria including the pathogenic Mycobacterium tuberculosis. D29 encodes LysA endolysin, which hydrolyzes mycobacterial cell wall peptidoglycan. We previously showed that LysA harbors two catalytic domains (N-terminal domain [NTD] and lysozyme-like domain [LD]) and a C-terminal cell wall binding domain (CTD). While the importance of LD and CTD in mycobacteriophage biology has been examined in great detail, NTD has largely remained unexplored. Here, to address NTD's significance in D29 physiology, we generated NTD-deficient D29 (D29∆NTD) by deleting the NTD-coding region from D29 genome using CRISPY-BRED. We show that D29∆NTD is viable, but has a longer latent period, and a remarkably reduced burst size and plaque size. A large number of phages were found to be trapped in the host during the D29∆NTD-mediated cell lysis event. Such poor release of progeny phages during host cell lysis strongly suggests that NTD-deficient LysA produced by D29∆NTD, despite having catalytically-active LD, is unable to efficiently lyse host bacteria. We thus conclude that LysA NTD is essential for optimal release of progeny virions, thereby playing an extremely vital role in phage physiology and phage propagation in the environment.

Mycobacteriophages: therapeutic approach for mycobacterial infections.

Tuberculosis (TB) is a significant global health threat, and cases of infection with non-tuberculous mycobacteria (NTM) causing lung disease (NTM-LD) are rising. Bacteriophages and their gene products have garnered interest as potential therapeutic options for bacterial infections. Here, we have compiled information on bacteriophages and their products that can kill Mycobacterium tuberculosis or NTM. We summarize the mechanisms whereby viable phages can access macrophage-resident bacteria and not elicit immune responses, review methodologies of pharmaceutical product development containing mycobacteriophages and their gene products, mainly lysins, in the context of drug regulatory requirements and we discuss industrially relevant methods for producing pharmaceutical products comprising mycobacteriophages, emphasizing delivery of mycobacteriophages to the lungs. We conclude with an outline of some recent case studies on mycobacteriophage therapy.

An intramolecular cross-talk in D29 mycobacteriophage endolysin governs the lytic cycle and phage-host population dynamics.

D29 mycobacteriophage encodes LysA endolysin, which mediates mycobacterial host cell lysis by targeting its peptidoglycan layer, thus projecting itself as a potential therapeutic. However, the regulatory mechanism of LysA during the phage lytic cycle remains ill defined. Here, we show that during D29 lytic cycle, structural and functional regulation of LysA not only orchestrates host cell lysis but also is critical for maintaining phage-host population dynamics by governing various phases of lytic cycle. We report that LysA exists in two conformations, of which only one is active, and the protein undergoes a host peptidoglycan-dependent conformational switch to become active for carrying out endogenous host cell lysis. D29 maintains a pool of inactive LysA, allowing complete assembly of phage progeny, thus helping avoid premature host lysis. In addition, we show that the switch reverses after lysis, thus preventing exogenous targeting of bystanders, which otherwise negatively affects phage propagation in the environment.

Removal of Six Esophageal Metals in a Four-Month-Old Infant: A Rare Case.

This case report details the distinctive and demanding clinical situation involving a four-month-old female neonate. Her chief complaint was a two-day refusal to consume food orally, accompanied by episodes of vomiting following feedings and a sensation of choking in the throat. The referring physician suspected the presence of a foreign body in the patient's esophagus and advised a chest X-ray following a thorough examination. The presence of six hyperdense metallic foreign bodies in the upper, mid, and distal dorsal esophagus was confirmed by subsequent CT thorax imaging. This case was managed through the implementation of a multidisciplinary strategy. A decision was reached to conduct an endoscopic assessment; a substantial foreign object resembling a boulder was detected throughout the procedure, resulting in total obstruction of the esophageal lumen. Despite some challenges, this foreign object was effectively extracted by utilizing a Dormia basket. After that, endoscopy was used to detect five more metallic foreign bodies, all successfully eliminated endoscopically. The postoperative course was characterized by the 24-hour prophylactic Ryles tube insertion, followed by the resumption of breastfeeding. The infant's recovery and positive attitude on the second day following the operation indicate the case's successful resolution, emphasizing the criticality of a timely intervention in similar circumstances. This report underscores the clinical management and treatment of multiple metallic foreign bodies in a pediatric patient while also stressing the importance of prompt diagnosis and interprofessional collaboration in complex and exceptional cases.

Deciphering the molecular mechanism and regulation of formaldehyde detoxification in Mycobacterium smegmatis.

The build-up of formaldehyde, a highly reactive molecule is cytotoxic and must be eliminated for the organism's survival. Formaldehyde detoxification system is found in nearly all organisms including both pathogenic and non-pathogenic mycobacteria. MscR, a formaldehyde dehydrogenase from Mycobacterium smegmatis (Msm), is an indispensable part of this system and forms a bicistronic operon with its downstream uncharacterized gene, fmh. We here show that Fmh, a putative metallo-beta-lactamase, is essential in tolerating higher amounts of formaldehyde when co-overexpressed with mscR in vivo. Our NMR studies indicate that MscR, along with Fmh, enhances formate production through a mycothiol (MSH)-dependent pathway, emphasizing the importance of Fmh in detoxifying formaldehyde. Although another aldehyde dehydrogenase, MSMEG_1543, induces upon formaldehyde addition, it is not involved in its detoxification. We also show that the expression of the mscR operon is constitutive and remains unchanged upon formaldehyde addition, as displayed by the promoter activity of PmscR and by the transcript and protein levels of MscR. Furthermore, we establish the role of a thiol-responsive sigma factor SigH in formaldehyde detoxification. We show that SigH, and not SigE, is crucial for formaldehyde detoxification, even though it does not directly regulate mscR operon expression. In addition, sensitivity to formaldehyde in sigH-knockout could be alleviated by overexpression of mscR. Taken together, our data demonstrate the importance of MSH-dependent pathways in detoxifying formaldehyde in a mycobacterial system. An absence of such MSH-dependent proteins in eukaryotes and its complete conservation in M. tuberculosis, the causative agent of tuberculosis, further unravel new drug targets for this pathogen.IMPORTANCEExtensive research has been done on formaldehyde detoxification in different bacteria. However, our current understanding of the mechanisms underlying this process in mycobacteria remains exceedingly little. We previously showed that MscR, a formaldehyde dehydrogenase from Mycobacterium smegmatis, plays a pivotal role in this detoxification pathway. Here, we present a potential S-formyl-mycothiol hydrolase named Fmh, thought to be a metallo-beta-lactamase, which functions along with mycothiol (MSH) and MscR to enhance formate production within this detoxification pathway. Co-expression of Fmh with MscR significantly enhances the efficiency of formaldehyde detoxification in M. smegmatis. Our experiments establish that Fmh catalyzes the final step of this detoxification pathway. Although an alternative sigma factor SigH was found to be involved in formaldehyde detoxification, it did not directly regulate the expression of mscR. Since formaldehyde detoxification is essential for bacterial survival, we envisage this process to be a potential drug target for M. tuberculosis eradication.

ACR Appropriateness Criteria® Staging and Post-Therapy Assessment of Head and Neck Cancer.

Imaging of head and neck cancer at initial staging and as part of post-treatment surveillance is a key component of patient care as it guides treatment strategy and aids determination of prognosis. Head and neck cancer includes a heterogenous group of malignancies encompassing several anatomic sites and histologies, with squamous cell carcinoma the most common. Together this comprises the seventh most common cancer worldwide. At initial staging comprehensive imaging delineating the anatomic extent of the primary site, while also assessing the nodal involvement of the neck is necessary. The treatment of head and neck cancer often includes a combination of surgery, radiation, and chemotherapy. Post-treatment imaging is tailored for the evaluation of treatment response and early detection of local, locoregional, and distant recurrent tumor. Cross-sectional imaging with CT or MRI is recommended for the detailed anatomic delineation of the primary site. PET/CT provides complementary metabolic information and can map systemic involvement. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Tinnitus: 2023 Update.

Tinnitus is abnormal perception of sound and has many subtypes. Clinical evaluation, audiometry, and otoscopy should be performed before ordering any imaging, as the choice of imaging will depend on various factors. Type of tinnitus (pulsatile or nonpulsatile) and otoscopy findings of a vascular retrotympanic lesion are key determinants to guide the choice of imaging studies. High-resolution CT temporal bone is an excellent tool to detect glomus tumors, abnormal course of vessels, and some other abnormalities when a vascular retrotympanic lesion is seen on otoscopy. CTA or a combination of MR and MRA/MRV are used to evaluate arterial or venous abnormalities like dural arteriovenous fistula, arteriovenous malformation, carotid stenosis, dural sinus stenosis, and bony abnormalities like sigmoid sinus wall abnormalities in cases of pulsatile tinnitus without a vascular retrotympanic lesion. MR of the brain is excellent in detecting mass lesions such as vestibular schwannomas in cases of unilateral nonpulsatile tinnitus. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Recent Advances of Multifunctional PLGA Nanocarriers in the Management of Triple-Negative Breast Cancer.

Even though chemotherapy stands as a standard option in the therapy of TNBC, problems associated with it such as anemia, bone marrow suppression, immune suppression, toxic effects on healthy cells, and multi-drug resistance (MDR) can compromise their effects. Nanoparticles gained paramount importance in overcoming the limitations of conventional chemotherapy. Among the various options, nanotechnology has appeared as a promising path in preclinical and clinical studies for early diagnosis of primary tumors and metastases and destroying tumor cells. PLGA has been extensively studied amongst various materials used for the preparation of nanocarriers for anticancer drug delivery and adjuvant therapy because of their capability of higher encapsulation, easy surface functionalization, increased stability, protection of drugs from degradation versatility, biocompatibility, and biodegradability. Furthermore, this review also provides an overview of PLGA-based nanoparticles including hybrid nanoparticles such as the inorganic PLGA nanoparticles, lipid-coated PLGA nanoparticles, cell membrane-coated PLGA nanoparticles, hydrogels, exosomes, and nanofibers. The effects of all these systems in various in vitro and in vivo models of TNBC were explained thus pointing PLGA-based NPs as a strategy for the management of TNBC.

Fisetin-Loaded Nanostructured Lipid Carriers: Formulation and Evaluations against Advanced and Metastatic Melanoma.

Fisetin (Fis), a natural flavonoid with anticancer effects, suffers from delivery constraints. Fisetin-nanostructured lipid carriers (NLCs) were developed for better efficacy against metastatic melanoma, employing the design of experiment (DoE) approach. The optimized NLCs depict a particle diameter of 135.0 ± 5.5 nm, a polydispersity index (PDI) of 0.176 ± 0.035, and an entrapment efficiency of 78.16 ± 1.58%. The formulation was stable over a period of 60 days and demonstrated sustained release of the drug (74.79 ± 3.75%) over 96 h. Fis-NLCs depicted at least ∼3.2 times lower IC50 value and ∼1.8 times higher drug uptake at 48 h in A-375 and B16F10 cells compared to that of Fis. It also inhibited the mobility of melanoma cells and induced cell cycle arrest at the G1/S phase. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot results show enhanced expression of Nrf2/NQO1 genes and an apoptotic effect by the upregulation of BAX mRNA expression. The protein levels of BAX and p53 were ∼2-fold higher compared with that of pure Fis. In-vivo studies demonstrated 5.9- and 10.7-fold higher inhibition in melanoma-associated metastasis in the lungs and liver, respectively. The outcomes from this study demonstrated Fis-NLCs as an effective tool against melanoma.

The multifaceted role of extracellular vesicles in prostate cancer-a review.

Prostate cancer is the second most prominent form of cancer in men and confers the highest mortality after lung cancer. The term "extracellular vesicles" refers to minute endosomal-derived membrane microvesicles and it was demonstrated that extracellular vesicles affect the environment in which tumors originate. Extracellular vesicles' involvement is also established in the development of drug resistance, angiogenesis, stemness, and radioresistance in various cancers including prostate cancer. Extracellular vesicles influence the general environment, processes, and growth of prostate cancer and can be a potential area that offers a significant lead in prostate cancer therapy. In this review, we have elaborated on the multifaceted role of extracellular vesicles in various processes involved in the development of prostate cancer, and their multitude of applications in the diagnosis and treatment of prostate cancer through the encapsulation of various bioactives.

Mycobacteriophage D29 Lysin B exhibits promising anti-mycobacterial activity against drug-resistant Mycobacterium tuberculosis.

IMPORTANCE: To combat the rapidly emerging drug-resistant M. tuberculosis, it is now essential to look for alternative therapeutics. Mycobacteriophages can be considered as efficient therapeutics due to their natural ability to infect and kill mycobacteria including M. tuberculosis. Here, we have exploited the mycolyl-arabinogalactan esterase property of LysB encoded from mycobacteriophage D29. This study is novel in terms of targeting a multi-drug-resistant pathogenic strain of M. tuberculosis with LysB and also examining the combination of anti-TB drugs and LysB. All the experiments include external administration of LysB. Therefore, the remarkable lytic activity of LysB overcomes the difficulty to enter the complex cell envelope of mycobacteria. Targeting the intracellularly located M. tuberculosis by LysB and non-toxicity to macrophages take the process of the development of LysB as a drug one step ahead, and also, the interaction studies with rifampicin and isoniazid will help to form a new treatment regimen against tuberculosis.

An Overview of Nanostructured Lipid Carriers and its Application in Drug Delivery through Different Routes.

Nanostructured Lipid Carriers (NLC) are nano-sized colloidal drug delivery system that contains a lipid mixture consisting of both solid and liquid lipids in their core. This Lipid-Based Nanosystem is introduced as a biocompatible, non-toxic, and safe nano-drug delivery system as compared to polymeric or metallic nanoparticles. Due to its safety, stability, and high drug loading capacity compared to other lipid-based nanocarriers, NLC gained the attention of researchers to formulate safe and effective drug carriers. The ability to increase drug solubility and permeability while encapsulating the drug in a lipidic shell makes them an ideal carrier for drug delivery through difficult-to-achieve routes. Surface modification of NLC and the use of various additives result in drug targeting and increased residence time. With such qualities, NLCs can be used to treat a variety of diseases such as cancer, infections, neurodegenerative diseases, hypertension, diabetes, and pain management. This review focuses on the recent developments being made to deliver the drugs and genes through different routes via these nanocarriers. Here, we also discuss about historical background, structure, types of NLC and commonly employed techniques for manufacturing lipid-based nanocarriers.

F3 peptide functionalized liquid crystalline nanoparticles for delivering Salinomycin against breast cancer.

Salinomycin (Sal) is a potent veterinary antibiotic known to offer significant toxicity to the variety of neoplastic cells. Its therapeutic utility is limited due to its higher lipophilicity (logP 7.5) and poor hydrophilicity. Liquid crystalline nanoparticles (LCNPs) known to offer a suitable delivery platform for these kinds of drugs. The overexpressed nucleolin receptor on the cell surface and cytoplasm, could be selected as a target in cancer therapy. The present study involves the development and characterization of the F3 peptide functionalized LCNPs for delivering Sal (F3-Sal-NPs) for selectively targeting to the nucleolin receptor. The optimized LCNPs were characterized for particle size, zeta potential, surface morphology, drug release kinetics and stability. The LCNPs have a structure similar to nematic phases. In vitro drug release studies revealed sustained drug release characteristics (89.5 ± 1.5% at 120 h) with F3-Sal-NPs. The cytotoxicity results demonstrated that F3-Sal-NPs were 4.8, 2.6 and 5.5 folds more effective than naïve drug in MDA-MB-468, MDA-MB-231 and MCF-7 cells, respectively and the cell cycle was arrested in the S and G2/M phases. The expression of the gene responsible for the stemness (CD44 gene), apoptosis (BAX/Bcl-2 ration) and angiogenesis (LCN-2) was reduced by F3-Sal-NPs treatment. Ex vivo hemolytic toxicity was reduced (6.5 ± 1.5%) and the pharmacokinetics and bioavailability of Sal was improved with F3-Sal-NPs. The in vivo antitumor efficacy was tested in EAC bearing mice, where F3-Sal-NPs significantly reduced the tumor growth by 2.8-fold compared to pure Sal and induced necrosis of tumor cells. The results clearly demonstrate the outstanding performance of F3 peptide functionalized LCNPs for delivering Sal against breast cancer.

Angiopep-2 Grafted PAMAM Dendrimers for the Targeted Delivery of Temozolomide: In Vitro and In Vivo Effects of PEGylation in the Management of Glioblastoma Multiforme.

The present study was aimed to synthesize, characterize, and evaluate the angiopep-2 grafted PAMAM dendrimers (Den, G 3.0 NH2) with and without PEGylation for the targeted and better delivery approach of temozolomide (TMZ) for the management of glioblastoma multiforme (GBM). Den-ANG and Den-PEG2-ANG conjugates were synthesized and characterized by 1H NMR spectroscopy. The PEGylated (TMZ@Den-PEG2-ANG) and non-PEGylated (TMZ@Den-ANG) drug loaded formulations were prepared and characterized for particle size, zeta potential, entrapment efficiency, and drug loading. An in vitro release study at physiological (pH 7.4) and acidic pH (pH 5.0) was performed. Preliminary toxicity studies were performed through hemolytic assay in human RBCs. MTT assay, cell uptake, and cell cycle analysis were performed to evaluate the in vitro efficacy against GBM cell lines (U87MG). Finally, the formulations were evaluated in vivo in a Sprague-Dawley rat model for pharmacokinetics and organ distribution analysis. The 1H NMR spectra confirmed the conjugation of angiopep-2 to both PAMAM and PEGylated PAMAM dendrimers, as the characteristic chemical shifts were observed in the range of 2.1 to 3.9 ppm. AFM results revealed that the surface of Den-ANG and Den-PEG2-ANG conjugates were rough. The particle size and zeta potential of TMZ@Den-ANG were observed to be 229.0 ± 17.8 nm and 9.06 ± 0.4 mV, respectively, whereas the same for TMZ@Den-PEG2-ANG were found to be 249.6 ± 12.9 nm and 10.9 ± 0.6 mV, respectively. The entrapment efficiency of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were calculated to be 63.27 ± 5.1% and 71.48 ± 4.3%, respectively. Moreover, TMZ@Den-PEG2-ANG showed a better drug release profile with a controlled and sustained pattern at PBS pH 5.0 than at pH 7.4. The ex vivo hemolytic study revealed that TMZ@Den-PEG2-ANG was biocompatible in nature as it showed 2.78 ± 0.1% hemolysis compared to 4.12 ± 0.2% hemolysis displayed by TMZ@Den-ANG. The outcomes of the MTT assay inferred that TMZ@Den-PEG2-ANG possessed maximum cytotoxic effects against U87MG cells with IC50 values of 106.62 ± 11.43 µM (24 h) and 85.90 ± 9.12 µM (48 h). In the case of TMZ@Den-PEG2-ANG, the IC50 values were reduced by 2.23-fold (24 h) and 1.36-fold (48 h) in comparison to pure TMZ. The cytotoxicity findings were further confirmed by significantly higher cellular uptake of TMZ@Den-PEG2-ANG. Cell cycle analysis of the formulations suggested that the PEGylated formulation halts the cell cycle at G2/M phase with S-phase inhibition. In the in vivo studies, the half-life (t1/2) values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were enhanced by 2.22 and 2.76 times, respectively, than the pure TMZ. After 4 h of administration, the brain uptake values of TMZ@Den-ANG and TMZ@Den-PEG2-ANG were found to be 2.55 and 3.35 times, respectively, higher than that of pure TMZ. The outcomes of various in vitro and ex vivo experiments promoted the use of PEGylated nanocarriers for the management of GBM. Angiopep-2 grafted PEGylated PAMAM dendrimers can be potential and promising drug carriers for the targeted delivery of antiglioma drugs directly to the brain.

Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics.

Cancer is one of the major causes of mortality, globally. Cancerous cells invade normal cells and metastasize to distant sites with the help of the lymphatic system. There are several mechanisms involved in the development and progression of cancer. Several treatment strategies including the use of phytoconstituents have evolved and been practiced for better therapeutic outcomes against cancer. Fisetin is one such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, and anticancer properties. It inhibits the rapid growth, invasiveness, and metastasis of tumors by hindering the multiplication of cancer cells, and prompts apoptosis by avoiding cell division related to actuation of caspase-9 and caspase-8. However, its poor bioavailability associated with its extreme hydrophobicity hampers its clinical utility. The issues related to fisetin delivery can be addressed by adapting to the developmental aspects of nanomedicines, such as formulating it into lipid or polymer-based systems, including nanocochleates and liposomes. This review aims to provide in-depth information regarding fisetin as a potential candidate for anticancer therapy, its properties and various formulation strategies.

Folate receptor targeted NIR cleavable liposomal delivery system augment penetration and therapeutic efficacy in breast cancer.

BACKGROUND: Liposomes are predominantly used sorts of nanocarriers for active a targeted delivery through surface functionalization using targeting ligand. The folate receptors are overexpressed in various cancers including breast cancer and because of its binding aptitude specifically to folate receptors, folic acid became the attractive ligand. METHODS: In this research, we have developed a folate and Poly-l-Lysine conjugate and coated this conjugate onto the liposomes. The prepared liposomes were characterized using DLS, FTIR, NMR, SEM, TEM, XRD, AFM, stability and drug release studies. Furthermore, in vitro studies were carried out on FR overexpressed breast cancer cell line. RESULTS: The FA-LUT-ABC-Lip have diameter of 183 ± 3.17 nm with positive surface charge +33.65 ± 3 mV and the drug release studies confirm the NIR responsive payload cleavage. The coated formulation (in presence of NIR light) effectively reduced the IC50 values and kills breast cancer cells through FR mediated internalization and accelerated drug release. Moreover, LUT Formulation shows anticancer effect due to significant inhibition of cell migration and proliferation by regulating VEGF expression and induced apoptosis through the caspase-3 up-regulation. CONCLUSION: It is evident from the in vitro studies that the formulation was found to be very effective and can be explored for triggered and targeted delivery of the substances through active targeting. GENERAL SIGNIFICANCE: Combining receptor mediated drug delivery with triggered release aid in more amounts of drug reaching the target site and achieving enhanced therapeutic activity.

Nanoconstructs for theranostic application in cancer: Challenges and strategies to enhance the delivery.

Nanoconstructs are made up of nanoparticles and ligands, which can deliver the loaded cargo at the desired site of action. Various nanoparticulate platforms have been utilized for the preparation of nanoconstructs, which may serve both diagnostic as well as therapeutic purposes. Nanoconstructs are mostly used to overcome the limitations of cancer therapies, such as toxicity, nonspecific distribution of the drug, and uncontrolled release rate. The strategies employed during the design of nanoconstructs help improve the efficiency and specificity of loaded theranostic agents and make them a successful approach for cancer therapy. Nanoconstructs are designed with a sole purpose of targeting the requisite site, overcoming the barriers which hinders its right placement for desired benefit. Therefore, instead of classifying modes for delivery of nanoconstructs as actively or passively targeted systems, they are suitably classified as autonomous and nonautonomous types. At large, nanoconstructs offer numerous benefits, however they suffer from multiple challenges, too. Hence, to overcome such challenges computational modelling methods and artificial intelligence/machine learning processes are being explored. The current review provides an overview on attributes and applications offered by nanoconstructs as theranostic agent in cancer.

Canal narrowing in adult patients with cervical spinal cord injury without computed tomography evidence of trauma.

PURPOSE: Cervical spinal cord injury can be a particularly devastating sequela of trauma. The purpose of this study was to describe the imaging findings of adult patients with cervical spinal cord injury without computed tomography evidence of trauma (SCIWOCTET). METHODS: All adult patients (≥18 years) treated for acute cervical SCIWOCTET at a single Level I adult trauma center over an eight-year period were retrospectively identified. CT imaging was evaluated for degenerative changes narrowing the midsagittal canal diameter (SCD) of the cervical spine and relative congenital cervical stenosis (CCS; congenital narrowing of the SCD <13 mm). Magnetic resonance imaging (MRI) scans were evaluated for signal intensity change (SIC) suspicious for cord edema/contusion as well as ligamentous injury, hemorrhage, and epidural hematoma. RESULTS: Ninety-six patients with cervical SCIWOCTET met inclusion criteria. The most common mechanism of injury was fall from standing (47.9%). On CT, 86 patients (89.6%) had CCS. Degenerative changes were present in 95 patients (99.0%). In 98/99 patients (99.0%), the point of narrowest cervical SCD was ≤8 mm. On MRI, 79 patients (82.3%) demonstrated signal intensity change (SIC) indicative of cord edema/contusion, while 16 (16.7%) had ligamentous injury. Intramedullary cord hemorrhage was seen in two patients (2.1%) and epidural hematoma in three (3.1%). CONCLUSION: Degenerative changes or CCS may narrow the minimum cervical SCD beyond the threshold at which low-energy trauma results in C-SCI. Adult patients with cervical spinal stenosis, whether congenital and/or degenerative, and neurologic findings referable to the cervical spine should be assessed for C-SCI.