T2-Fluid-attenuated inversion recovery (FLAIR) pseudoprogression in patients with anaplastic oligodendrogliomas treated with procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

BACKGROUND: Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone. METHODS: We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression. RESULTS: We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography (18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free. CONCLUSIONS: Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.

Psychological Adjustment Profiles of LGBTQ+ Young Adults Residing with Their Parents during the COVID-19 Pandemic: An International Study.

The COVID-19 pandemic has been associated with poor mental health symptoms, particularly among vulnerable populations such as LGBTQ+ individuals. In the present study, we aimed to (i) identify different psychological adjustment profiles among LGBTQ+ young adults during the COVID-19 pandemic and compare LGBTQ+ young adults in relation to (ii) sociodemographic characteristics and COVID-19-related experiences and (iii) the internal and external protective resources associated with each adjustment profile. An online questionnaire was administered to 1699 LGBTQ+ young adults from six countries (Brazil, Chile, Italy, Portugal, Sweden, and the UK). A cluster analysis was conducted, and four profiles of psychological adjustment were identified: unchallenged, resilient, distressed, and at-risk. The at-risk cluster scored lowest in social support (particularly from family). The profiles of participants who experienced the highest levels of pandemic adversity (at-risk and resilient) comprised mostly South American participants, those under lockdown at the time of survey completion, those who self-identified as transgender and non-binary, and those with a plurisexual sexual orientation. Interventions should consider strategies to help young adults maintain support systems and reinforce the value of positive family relationships. Specific groups within the LGBTQ+ community that seem to be in a particularly vulnerable situation may need additional tailored support.

Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. METHODS: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. RESULTS: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). CONCLUSIONS: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.

Nivolumab and Ipilimumab-induced myositis and myocarditis mimicking a myasthenia gravis presentation.

The rapidly growing field of cancer immunotherapy has led to the development of new treatments such as immune checkpoint inhibitors. These agents are monoclonal antibodies that enable tumor-reactive T cells to overcome regulatory mechanisms and produce effective antitumor responses. The use of immune checkpoint inhibitors is expected to progressively increase because they have shown promising therapeutic outcomes in multiple types of cancer and clinicians should be aware of their possible side-effects. We report a case of a man diagnosed with a non-microcytic lung carcinoma who started treatment with a combination of immune checkpoint inhibitors (Nivolumab and Ipilimumab). He subsequently developed binocular diplopia, fatigue, mild dyspnea and upper back pain resembling a myasthenia gravis presentation. Finally, a diagnosis of immune checkpoint inhibitor-related myositis and myocarditis was made. The detection of GFAP antibodies in CSF has unclear clinical and pathogenic significance and they may rather represent an epiphenomenon of the immune inflammation process.

A Theoretical Study of 8-Chloro-9-Hydroxy-Aflatoxin B1, the Conversion Product of Aflatoxin B1 by Neutral Electrolyzed Water.

Theoretical studies of 8-chloro-9-hydroxy-aflatoxin B1 (2) were carried out by Density Functional Theory (DFT). This molecule is the reaction product of the treatment of aflatoxin B1 (1) with hypochlorous acid, from neutral electrolyzed water. Determination of the structural, electronic and spectroscopic properties of the reaction product allowed its theoretical characterization. In order to elucidate the formation process of 2, two reaction pathways were evaluated-the first one considering only ionic species (Cl⁺ and OH(-)) and the second one taking into account the entire hypochlorous acid molecule (HOCl). Both pathways were studied theoretically in gas and solution phases. In the first suggested pathway, the reaction involves the addition of chlorenium ion to 1 forming a non-classic carbocation assisted by anchimeric effect of the nearest aromatic system, and then a nucleophilic attack to the intermediate by the hydroxide ion. In the second studied pathway, as a first step, the attack of the double bond from the furanic moiety of 1 to the hypochlorous acid is considered, accomplishing the same non-classical carbocation, and again in the second step, a nucleophilic attack by the hydroxide ion. In order to validate both reaction pathways, the atomic charges, the highest occupied molecular orbital and the lowest unoccupied molecular orbital were obtained for both substrate and product. The corresponding data imply that the C9 atom is the more suitable site of the substrate to interact with the hydroxide ion. It was demonstrated by theoretical calculations that a vicinal and anti chlorohydrin is produced in the terminal furan ring. Data of the studied compound indicate an important reduction in the cytotoxic and genotoxic potential of the target molecule, as demonstrated previously by our research group using different in vitro assays.

Synthesis of cycloveratrylene macrocycles and benzyl oligomers catalysed by bentonite under microwave/infrared and solvent-free conditions.

Tonsil Actisil FF, which is a commercial bentonitic clay, promotes the formation of cycloveratrylene macrocycles and benzyl oligomers from the corresponding benzyl alcohols in good yields under microwave heating and infrared irradiation in the absence of solvent in both cases. The catalytic reaction is sensitive to the type of substituent on the aromatic ring. Thus, when benzyl alcohol was substituted with a methylenedioxy, two methoxy or three methoxy groups, a cyclooligomerisation process was induced. Unsubstituted, methyl and methoxy benzyl alcohols yielded linear oligomers. In addition, computational chemistry calculations were performed to establish a validated mechanistic pathway to explain the growth of the obtained linear oligomers.

DFT and docking studies of rhodostreptomycins A and B and their interactions with solvated/nonsolvated Mg²âº and Ca²âº ions.

The interactions of L-aminoglucosidic stereoisomers such as rhodostreptomycins A (Rho A) and B (Rho B) with cations (Mg(2+), Ca(2+), and H(+)) were studied by a quantum mechanical method that utilized DFT with B3LYP/6-311G. Docking studies were also carried out in order to explore the surface recognition properties of L-aminoglucoside with respect to Mg(2+) and Ca(2+) ions under solvated and nonsolvated conditions. Although both of the stereoisomers possess similar physicochemical/antibiotic properties against Helicobacter pylori, the thermochemical values for these complexes showed that its high affinity for Mg(2+) cations caused the hydration of Rho B. According to the results of the calculations, for Rho A-Ca(2+)(H2O)6, ΔH = -72.21 kcal mol(-1); for Rho B-Ca(2+)(H2O)6, ΔH = -72.53 kcal mol(-1); for Rho A-Mg(2+)(H2O)6, ΔH = -72.99 kcal mol(-1) and for Rho B-Mg(2+)(H2O)6, ΔH = -95.00 kcal mol(-1), confirming that Rho B binds most strongly with hydrated Mg(2+), considering the energy associated with this binding process. This result suggests that Rho B forms a more stable complex than its isomer does with magnesium ion. Docking results show that both of these rhodostreptomycin molecules bind to solvated Ca(2+) or Mg(2+) through hydrogen bonding. Finally, Rho B is more stable than Rho A when protonation occurs.

Acid-catalyzed nucleophilic additions to carbonyl groups: is the accepted mechanism the rule or an exception?

The transesterification reaction, and in particular the methanolysis of ethyl acetate with sulfuric acid as catalyst, is used as a model reaction to study the acid-catalyzed nucleophilic addition to a carbonyl group. Continuum solvation methods (SMD and IEF-PCM) and the MPWB1K functional are used. The reaction mechanism is studied in methanol and in acetonitrile as solvents. Our results indicate that the acid-catalyzed addition mechanism is stepwise, and the transition state (TS) is a contact ion-pair. The counteranion of the acid catalyst remains in the reaction site playing an important role in the TS of this reaction. Changes in the reaction kinetics and the ionic/nonionic nature of the TS with the ionizing ability of the solvent and the strength of the acid catalyst are explored. Additional calculations at the CBS-Q3 level of theory reinforce the conclusions of this paper. The results obtained allow the generalization of important ideas regarding the mechanism of the nucleophilic addition to carbonyl groups.

Effects of bentonite on p-methoxybenzyl acetate: a theoretical model for oligomerization via an electrophilic-substitution mechanism.

Tonsil Actisil FF, a commercial bentonitic clay, promotes the formation of a series of electrophilic-aromatic-substitution products from para-methoxybenzyl acetate in carbon disulfide. The molecules obtained correspond to linear isomeric dimers, trimers, tetramers and a pentamer, according to their spectroscopic data. A clear indication of the title mechanistic pathway for the oligomerization growth was obtained from the analysis of a set of computational-chemistry calculations using the density-functional-theory level B3LYP/6-311++G(d,p). The corresponding conclusions were based on the computed dipole moments, the HOMO/LUMO distributions, and a natural-populations analysis of the studied molecules.

In vitro biological effects of airborne PM2.5 and PM10 from a semi-desert city on the Mexico-US border.

Compelling evidence indicates that exposure to urban airborne particulate matter (PM) affects health. However, how PM components interact with PM-size to cause adverse health effects needs elucidation, especially when considering soil and anthropogenic sources. We studied PM from Mexicali, Mexico, where soil particles contribute importantly to air pollution, expecting to differentiate in vitro effects related to PM-size and composition. PM samples with mean aerodynamic diameters ≤2.5µm (PM(2.5)) and ≤10µm (PM(10)) were collected in Mexicali (October 2005-March 2006) from a semi-urban (expected larger participation of soil sources) and an urban (predominately combustion sources) site. Samples were pooled by site and size, analyzed for elemental composition (particle-induced X-ray emission) and tested in vitro for: induction of human erythrocytes membrane disruption (hemolysis) (colorimetrically); inhibition of cell proliferation (ICP) (crystal violet) and TNFα/IL-6 secretion (ELISA) using J774.A1 murine monocytic cells; and DNA degradation using Balb/c3T3 cell naked DNA (electrophoretically). Results of PM elemental composition principal component analysis were used in associating cellular effects. Sixteen elements identified in PM grouped in two principal components: Component(1) (C(1)): Mg, Al, Si, P, Cl, K, Ca, Ti, V, Cr, Fe, and Component(2) (C(2)): Cu, Zn. Hemolysis was predominately induced by semi-urban-PM(10) (p<0.05) and was associated with urban-PM(10)C(1) (r=0.62, p=0.003). Major ICP resulted with semi-urban PM(2.5) (p<0.05). TNFα was mainly induced by urban samples regardless of size (p<0.05) and associated with urban-PM(2.5)C(2) (r=0.48, p=0.02). Both PM(10) samples induced highest DNA degradation (p<0.05), regardless of location. We conclude that PM-size and PM-related soil or anthropogenic elements trigger specific biological-response patterns.

Gingival mucinous adenocarcinoma of a minor salivary gland.

BACKGROUND: A 47-year-old male non-smoker with a history of psoriasis sought a consultation because of a painless, hard-on-palpation, 1-cm exophytic lesion with a smooth and speckled surface located on the hard palate adjacent to tooth #12. The radiologic examination revealed no bone destruction. The lesion was clinically diagnosed as a fibrous hyperplasia or chronic pyogenic granuloma. METHODS: The lesion was surgically removed, fixed in 10% neutral buffered formalin for 24 hours, and, following common practice, embedded in paraffin. Sections, 4 mum thick, were stained with hematoxylin and eosin, periodic acid-Schiff, and alcian blue, pH 2.5. An immunohistochemical study was also performed. RESULTS: A definitive diagnosis of a mucinous adenocarcinoma (MAC), a very rare, high-grade malignancy tumor that more frequently appears in the elderly, was made. With the definitive diagnosis of an MAC of the palate, the upper-left premolars were extracted using a box osteotomy, and the surgical wound was reconstructed with a Bichat fat-pad flap. After a 6-month follow-up, no recurrence or cervical metastases were identified. CONCLUSIONS: An MAC of a minor salivary gland may arise as a gingival exophytic lesion with a clinical appearance similar to a pyogenic granuloma. The existence of a light speckled pattern on the surface of the lesion indicates that an incisional biopsy is needed before surgical treatment to make possible a definitive diagnosis. To avoid delays in diagnosis and erroneous clinical approaches to exophytic gingival lesions, periodontists and practitioners should routinely perform a pathologic analysis to confirm the diagnosis when dealing with these kinds of lesions.

Role of lactone ring in structural, electronic, and reactivity properties of aflatoxin B1: a theoretical study.

This study involved quantum mechanical calculations to explain the chemical behavior of the lactone ring of aflatoxin B1, which is a carcinogenic hazardous compound. The aflatoxin B1 compound, produced by the fungi Aspergillum flavus, was studied with the B3LYP/6-311+G(d,p) method; its reactivity properties were accounted for by means of the calculated geometrical and electronic parameters. The results obtained indicate that the fused A, B, C, and D rings of aflatoxin adopt a continuous planar conformation. The carbon atom of the lactone group presents a highly electrophilic character, since the population analysis yields a high positive charge for this atom, whereas high negative charges were recorded for both oxygen sites of that group. Thus, in an acidic aqueous medium, the oxygen atoms could be protonated and the carbon site may suffer a nucleophilic attack by water. Accordingly, the OC-O bond length has been lengthened substantially. So it was demonstrated that the lactonic ring of aflatoxin B1 is hydrolyzed under acidic conditions by an acid-acyl bimolecular mechanisms, A(AC)2, suggesting the deletion of its carcinogenic properties.

Proliferative activity and diagnostic delay in oral cancer.

BACKGROUND: Tumor stage may relate to the chronology of neoplasm growth and has been used as an outcome variable when studying diagnostic delay in oral cancer. However, tumor growth rate may act as a confounding factor. METHODS: We reviewed a total of 63 incident cases of oral cancer. The variables considered for the study included age, sex, smoking history, tumor site, TNM stage, Ki-67 score, and diagnostic delay. RESULTS: Significant differences between survivors and exitus were found in terms of tumor stage at diagnosis (I-II vs III-IV), sex, and Ki-67 scores. When the analysis was adjusted for tumor stage at diagnosis (I-II vs III-IV), proliferative activity resulted to be an independent prognostic factor for survival, whereas diagnostic delay did not influence survival. CONCLUSION: These results seem to suggest that survival from oral cancer is affected more by the biology of the cancer (rapid tumor growth) than by diagnostic delay.

Theoretical Study of Intramolecular, CH [Formula: see text] X (X = N, O, Cl), Hydrogen Bonds in Thiazole Derivatives.

CH [Formula: see text] X (X = N, O, or Cl) hydrogen bonds formed intramolecularly in 2-methyl-4-(2-chloro-4,5-dimethoxyphenyl)thiazole (Ia), 2-amino-4-(2-chloro-4,5-dimethoxy phenyl)thiazole (Ib), 2-amino-4-(2,4,5-trimethoxyphenyl)thiazole (Ic), and 2-methyl-4-(2,4,5-trimethoxyphenyl)thiazole (Id) were studied by means of all-electron calculations performed with the B3LYP/6-311++G(d,p) method. Computed ground states, in the gas phase, show the presence of a single H-bond, CH [Formula: see text] Cl, in each Ia and Ib moiety, and two H-bonds, CH [Formula: see text] N and CH [Formula: see text] O, for each Ic and Id molecule. H [Formula: see text] Cl, H [Formula: see text] N, and H [Formula: see text] O distances are shorter than the sum of the X and H van der Waals radii. H-bond energies of ≅2.0 kcal/mol were estimated for Ia and Ib and ≅4.0 kcal/mol for Ic and Id. These results agree with those of the theory of atoms in molecules, since bond critical points were found for these H [Formula: see text] X bonds. Finally, the chemical shifts in the (1)H NMR were calculated by the GIAO method; in Ia and Ib they are merely due to the different topological positions of the H atoms. But in Ic and Id the shifts of H [Formula: see text] N and H [Formula: see text] O have signatures of H-bond formations.

Gingival squamous cell carcinoma: diagnostic delay or rapid invasion?

BACKGROUND: The similarity between gingival squamous cell carcinoma (GSCC) and more common periodontal lesions may lead to a delay in diagnosis or misdiagnosis. Neoplastic lesions of gingival tissues are frequently diagnosed at an advanced stage. METHODS: To assess the relative time from when patients first become aware of the problem to histopathologic diagnosis (total diagnostic time), 59 consecutive oral cancer cases were examined in this study. The following variables were considered: age, gender, smoking habits, tumor stage at diagnosis, and total diagnostic time. The median of the patients' total diagnostic time (1.5 months) was used as a cutoff point to distinguish between delayed and non-delayed cases. Analysis of the variables was undertaken using the Student t test and chi2 test, with a 95% confidence interval (CI). RESULTS: The total diagnostic time was <1.5 months for 75% of gingival carcinomas, 50% of tongue carcinomas, and 78% of floor-of-the-mouth carcinomas. It was >1.5 months for 25% of gingival carcinomas, 50% of tongue carcinomas, and 21% of floor-of-the-mouth carcinomas. No significant differences in time before diagnosis were found when gingival cancers were compared to other oral tumors (chi2=0.21; 95% CI=-0.40 to 0.26). However, by the time of diagnosis, gingival cancers had invaded adjacent structures more frequently than other oral cancers (chi2=13.51; 95% CI=0.18 to 0.85). CONCLUSIONS: The gingival location of oral squamous cell carcinoma (OSCC) was associated with advanced stages at the time of diagnosis, due to early invasion of contiguous bone tissue (T4-primary tumor). This would indicate that even earlier referral and diagnosis are necessary.