Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps.

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting. Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored). Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in VBlue/VCE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes. Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

Exploiting the Different Nucleophilicity of the Isocyano Group: A Strategy for the Isocyanide Functionalization.

By exploiting the different nucleophilicity of aromatic and aliphatic isocyanides, we selectively react aliphatic isocyano groups while preserving aromatic ones in Passerini and Ugi multicomponent reactions. This simple approach allows the synthesis of α-acyloxy carboxamides or α-acylamino carboxamides possessing one or two isocyanide groups, which are challenging to achieve through traditional formylation and dehydration protocols. These analogues have the potential to serve as valuable building blocks with diverse applications.

Each Interruption is an Opportunity: Novel Synthetic Strategies Explored Through Interrupted Click Reactions.

The particular and unique mechanism of the copper-catalyzed reaction between azides and alkynes (CuAAC) has not only allowed for the efficient synthesis of 1,2,3-trisubstituted 1,4-triazoles in excellent yields and under mild conditions, becoming the quintessential click reaction, but it has also enabled the straightforward formation of a metallocycle intermediate, the copper triazolyl. This, under suitable reaction conditions able to suppress its protonolysis, can be used either for the creation of new bicyclic triazolyl structures or for the generation of novel three or four-component reactions. The aim of this review is to rationalize and unify all these transformations, which are collectively referred to as "interrupted click reactions".

Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists.

NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies. We herein report the expansion of the chemical space of NOD1 antagonists via a multicomponent synthetic approach affording a novel chemotype, namely, 2,3-diaminoindoles. These efforts resulted in compound 37, endowed with low micromolar affinity toward NOD1. Importantly, a proof-of-evidence of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination of computational studies and NMR-based displacement assays enabled the characterization of the binding modality of 37 to NOD1, thus providing key unprecedented knowledge for the design of potent and selective NOD1 antagonists.

eHydrogenation: Hydrogen-free Electrochemical Hydrogenation.

Hydrogenation reactions are staple transformations commonly used across scientific fields to synthesise pharmaceuticals, natural products, and various functional materials. However, the vast majority of these reactions require the use of a toxic and costly catalyst leading to unpractical, hazardous and often functionally limited conditions. Herein, we report a new, general, practical, efficient, mild and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro and azido groups. Finally, this method has been applied to deuterium labelling.

Isocyanides as Catalytic Electron Acceptors in the Visible Light Promoted Oxidative Formation of Benzyl and Acyl Radicals.

The recent disclosure of the ability of aromatic isocyanides to harvest visible light and act as single electron acceptors when reacting with tertiary aromatic amines has triggered a renewed interest in their application to the development of green photoredox catalytic methodologies. Accordingly, the present work explores their ability to promote the generation of both alkyl and acyl radicals starting from radical precursors such as Hantzsch esters, potassium alkyltrifluoroborates, and α-oxoacids. Mechanistic studies involving UV-visible absorption and fluorescence experiments, electrochemical measurements of the ground-state redox potentials along with computational calculations of both the ground- and the excited-state redox potentials of a set of nine different aromatic isocyanides provide key insights to promote a rationale design of a new generation of isocyanide-based organic photoredox catalysts. Importantly, the green potential of the investigated chemistry is demonstrated by a direct and easy access to deuterium labeled compounds.

Conventional and Advanced MRI Techniques in the Evaluation of Primary CNS Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin's lymphoma that accounts for 1%-5% of all central nervous system tumors. Contrast-enhanced MR is the imaging technique of choice. PCNLs have a predilection for the periventricular and superficial regions, often abutting the ventricular or meningeal surfaces. Although PCNLs may have characteristic imaging features on conventional MRI, none of these will unequivocally differentiate PCNSLs from other brain lesions. Diffusion restriction, relative hypoperfusion, increased choline/creatinine, decrease of N-acetyl aspartate (NAA) peak as well as the presence of lactate and lipid peaks are consistent advanced imaging findings in CNS lymphoma that may help in the differentiation of Primary central nervous system lymphomas (PCNSLs) from other malignancies. Furthermore, advanced imaging techniques will presumably play an important role in the planning of new targeted therapies, for prognostication, and for the monitoring of treatment response in the future.

Initial Experience Using the New pHLO 0.072-inch Large-Bore Catheter for Direct Aspiration Thrombectomy in Acute Ischemic Stroke.

PURPOSE: A direct aspiration, first pass technique (ADAPT) has been introduced as a rapid and safe thrombectomy strategy in patients with intracranial large vessel occlusion (LVO). The aim of the study is to determine the technical feasibility, safety, and functional outcome of ADAPT using the newly released large bore pHLO 0.072-inch aspiration catheter (AC; Phenox). MATERIALS AND METHODS: We performed a retrospective analysis of data collected prospectively (October 2019-November 2021) from 2 comprehensive stroke centers. Accessibility of the thrombus, vascular recanalization, time to recanalization, and procedure-related complications were evaluated. National Institutes of Health stroke scale scores at presentation and discharge and the modified Rankin scale (mRS) score at 90 days post-procedure were recorded. RESULTS: Twenty-five patients (14 female, 11 male) with occlusions of the anterior circulation were treated. In 84% of cases, ADAPT led to successful recanalization with a median procedure time of 28 minutes. In the remaining cases, successful recanalization required (to a total of 96%; modified thrombolysis in cerebral infarction score 2b/3) the use of stent retrievers. No AC-related complications were reported. Other complications included distal migration of the thrombus, requiring a stent-retriever, and symptomatic PH2 hemorrhage in 16% and 4%, respectively. After 3 months, 52% of the patients had mRS scores of 0-2 with an overall mortality rate of 20%. CONCLUSION: Results from our retrospective case series revealed that thrombectomy of LVOs with pHLO AC is safe and effective in cases of large-vessel ischemic stroke. Rates of complete or near-complete recanalization after the first pass with this method might be used as a new benchmark in future trials.

Domino synthesis of 5-aminoimidazoles from Strecker multicomponent adducts via ytterbium-promoted isocyanide insertion/5-exo-dig cyclization.

A new Lewis acid promoted domino isocyanide insertion/5-exo-dig cyclization of readily available Strecker 3-component adducts to 4-substituted 5-aminoimidazole derivatives is herein reported. Despite their potential as relevant heterocyclic scaffolds in medicinal chemistry programs, this class of compounds is still underrepresented, with current synthetic strategies poorly efficient in terms of timing and yields. To this end, we show how the exploitation of unconventional reactivities of isocyanides, promoted by ytterbium-triflate, could represent a key resource to enable a fast and easy access to such an unexplored area of the chemical space.

Visible-Light Photoredox Catalysis in Water.

The use of water in organic synthesis draws attention to its green chemistry features and its unique ability to unveil unconventional reactivities. Herein, literature about the use of water as a reaction medium under visible-light photocatalytic conditions is summarized in order to highlight challenges and opportunities. Accordingly, this Synopsis has been divided into four different sections focused on (1) the unconventional role of water in photocatalytic reactions, (2) in-/on-water reactions, (3) water-soluble photocatalysts, and (4) photomicellar catalytic systems.

Isocyanide-Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis.

Isocyanide-based multicomponent reactions claim a one century-old history of flourishing developments. On the other hand, the enormous impact of recent progresses in visible light photocatalysis has boosted the identification of new straightforward and green approaches to both new and known chemical entities. In this context, the application of visible light photocatalytic conditions to multicomponent processes has been promoting key stimulating advancements. Spanning from radical-polar crossover pathways, to photoinduced and self-catalyzed transformations, to reactions involving the generation of imidoyl radical species, the present literature analysis would provide a general and critical overview about the potentialities and challenges of exploiting isocyanides in visible light photocatalytic multicomponent reactions.

Imaging of Common Spinal Cord Diseases.

Spinal cord evaluation is an integral part of spine assessment, and its reliable imaging work-up is mandatory because even localized lesions may produce serious effects with potentially irreversible sequelae. Spinal cord alterations are found both incidentally during spine evaluation in otherwise neurologically asymptomatic patients or during neurologic/neuroradiologic assessment in myelopathic patients. Myelopathy (an umbrella term for any neurologic deficit that refers to spinal cord impairment) can be caused by intrinsic lesions or extrinsic mechanical compression, and its etiology may be both traumatic and/or nontraumatic. The symptoms largely depend on the size/extension of lesions, ranging from incontinence to ataxia, from spasticity to hyperreflexia, from numbness to weakness. Magnetic resonance imaging is the reference imaging modality in spinal cord evaluation, ensuring the best signal and spatial resolution. We provide an overview of the most common spinal cord disorders encountered by radiologists and describe the technical measures that offer optimal spinal cord visualization.

Photomicellar Catalyzed Synthesis of Amides from Isocyanides: Optimization, Scope, and NMR Studies of Photocatalyst/Surfactant Interactions.

The merging of micellar and photoredox catalysis represents a key issue to promote "in water" photochemical transformations. A photomicellar catalyzed synthesis of amides from N-methyl-N-alkyl aromatic amines and both aliphatic and aromatic isocyanides is herein presented. The mild reaction conditions enabled a wide substrate scope and a good functional groups tolerance, as further shown in the late-stage functionalization of complex bioactive scaffolds. Furthermore, solution 1D and 2D NMR experiments performed, for the first time, in the presence of paramagnetic probes enabled the study of the reaction environment at the atomic level along with the localization of the photocatalyst with respect to the micelles, thus providing experimental data to drive the identification of optimum photocatalyst/surfactant pairing.

The prognostic role of the pre-treatment neutrophil to lymphocyte ratio (NLR) and tumor depth of invasion (DOI) in early-stage squamous cell carcinomas of the oral tongue.

The appropriate surgical management of early-stage oral tongue squamous cell carcinoma (OTSCC) remains a debated topic. The aim of this study is to investigate the role of the pre-treatment neutrophil to lymphocyte ratio (NLR) and tumor depth of invasion (DOI) in predicting the presence of occult neck metastases in early-stage OTSCC. A retrospective analysis of patients affected by early-stage (cT1-T2 cN0) OTSCC who were submitted to elective neck dissection (END) was performed. Tumors were classified retrospectively according to the 8th TNM classification, the DOI was assessed on the pre-operative magnetic resonance imaging, and the pre-treatment NLR was calculated for each patient. A logistic regression model to estimate the probability π (x) of cervical metastases by studying the NLR and DOI was carried out. Next, the correlation between the two variables, the NLR and DOI, was preliminarily studied. A cohort of 110 patients was analyzed (mean age, 62 years old; male to female ratio 1.2:1). The patients were staged as cT1 in 53 cases and cT2 in 57 cases. A DOI greater than 5.4 mm and a NLR greater than 2.93 are associated with an increased risk of presenting occult cervical metastases. Furthermore, the variables NLR and DOI are linearly associated with a positive correlation, proved by Spearman's rank correlation coefficient rho of 0.64, with a unitary increase in the DOI of 1 mm directly associated with an increase of 0.47 in the NLR. The DOI and NLR can be effectively used to predict the occurrence of occult neck metastasis and therefore to plan an END in early-stage OTSCC.

Metanalysis on the effectiveness of low back pain treatment with oxygen-ozone mixture: Comparison between image-guided and non-image-guided injection techniques.

Low back pain (LBP) is a common disorder affecting an increasing number of people worldwide, whose diagnosis is focused on the identification of triggering causes. First line therapy usually starts from conservative approaches, whereas second line treatments include a spectrum of minimally invasive techniques, before resorting to more invasive surgical approaches. Among minimally invasive techniques, percutaneous oxygen-ozone injections represent one of the most common and cost-effective procedures. Aim of this study is to provide a metanalysis on literature evidences on percutaneous oxygen-ozone injections, comparing image-guided to non-image-guided techniques for LBP treatment. Imaging-guided procedures showed better performances compared to non-image-guided techniques based only on anatomical landmarks, with higher therapeutic efficacy and lower age-related variability in clinical results.

The Dark Side of Isocyanides: Visible-Light Photocatalytic Activity in the Oxidative Functionalization of C(sp3)-H Bonds.

The possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp3)-H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron-donor-acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N-phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts.

Enriching the Arsenal of Pharmacological Tools against MICAL2.

Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure-activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.

RESUMEN: A flexible class of multi-parameter qMRI protocols.

PURPOSE: To introduce a class of fast 3D quantitative MRI (qMRI) schemes (RESUMEN, for N=1,…,4) that allow for a thorough characterization of microstructural properties of brain tissues. METHODS: An arbitrary multi-echo GRE acquisition optimized for quantitative susceptibility mapping (QSM) is complemented with an appropriate low flip-angle GRE sequence drawn from four possible choices. The acquired signals are processed to analytically derive the longitudinal relaxation (R1) and free induction decay (R2∗) rates, as well as the proton density (PD) and QSM. A comprehensive modeling of the excitation and B1- profiles and of the RF-spoiling is included in the acquisition and processing pipeline. RESULTS: The RESUMEN maps appear homogeneous throughout the field-of-view and exhibit comparable values and high SNR across the considered range of N values. CONCLUSIONS: The introduced schemes represent a class of robust and flexible strategies to derive a thorough and fast qMRI study, suitable for a whole-brain acquisition with isotropic voxel resolution of 700 µm in less than 15 min.