Synthesis and biological evaluation of novel <Emphasis Type="SmallCaps">d</Emphasis>-glucose-derived 1,2,3-triazoles as potential antibacterial and antifungal agents

A series of novel d-glucose-derived 1,2,3-triazoles have been synthesized in excellent yields via Cu(I)-catalyzed 1,3-dipolar cycloaddition by using methyl α-d-glucopyranoside as starting material. All the new compounds were confirmed by ¹H NMR, ¹³C NMR, IR, MS, and HRMS spectra, and their antimicrobial activities were screened against Gram-Positive, Gram-Negative bacteria, and fungi. Bioactive assay manifested that some of the synthesized glucose-derived 1,2,3-triazoles exhibited good antibacterial and antifungal activities. Notably, compound 5k gave the most potent efficiency with MIC₅₀ value of 6 µM against Candida albicans, which was nine-fold more active than the reference drug Fluconazole. It also exhibited good antibacterial activity against Escherichia coli with the MIC₅₀ value of 10.8 µM compared to Chloramphenicol while the corresponding hydrochloride 4k revealed remarkable inhibitory against Bacillus subtilis with an MIC₅₀ value of 11 µM.     

Synthesis of new <Emphasis Type="Italic">O</Emphasis>-alkyl and alkyne–azide cycloaddition derivatives of 4′-methoxy licoflavanone: a distinct prenylated flavonoids depicting potent cytotoxic activity

Prenylated flavonoids represent a unique class of naturally occurring compounds and have proved to be an important source of chemically diverse novel metabolites. Nevertheless, they possess wild array of biological activities. 4′-Methoxy licoflavanone is a prenylated flavonoid isolated from stem bark of Erytherina subrossa. Herein, we report the synthesis of O-alkyl analogs (2a–2m) and 1,2,3 triazole conjugate (3–14) of 4′-methoxy licoflavanone by selective modification at C-7 position in the chromane nucleus. In addition, all the derivatives were evaluated for in vitro antiproliferative activity against a panel of cancer cell lines including pancreatic cancer (Mia PaCa-2), prostate cancer (PC-3), and human leukemia (HL-60) cells. The results revealed that some analogs including 2e and 2m exhibited better cytotoxicity effect than parent compound, specifically on Mia PaCa-2 cell lines.     

Drug induced oral erythema multiforme: Case report

Introduction:Drug induced oral erythema multiforme a rare clinical entity which involves only the lips and oral mucosa without skin involvement. These lesions are difficult in diagnosing with other oral ulcerative lesions with similar clinical manifestations.Patient concerns:This article presents 2 case reports of Oral erythema multiforme in which drugs were the precipitating factor. Its etiopathogenesis, differential diagnosis and treatment modalities of the disease is discussed.Diagnosis:Based on patient''s complaints, drug history and clinical appearance, provisional diagnosis of drug induced erythema multiforme was considered.Intervention:For case 1, patient was instructed to discontinue usage of drug and prescribed systemic steroid (Prednisolone 10 mg/d) for a week along with germicidal drugs to prevent secondary infection. Medication was tapered to 5 mg/d after first week.For case 2, patient was instructed to discontinue the drug and systemic steroid prednisolone 20 mg /d for 1 week with tapering dose of 10 mg/d for the second week was administered.Outcome:For case 1 and case 2 healing of the lesions were evident on third week of follow up.Conclusion:Medications should be taken under medical supervision. Over the counter drugs might lead to allergic reactions like drug induced oral erythema multiforme, which is a rare variant and needs to be differentiate from other oral ulcerative lesion for prompt management and follow-up.     

HIV's evasion of host's NK cell response and novel ways of its countering and boosting anti-HIV immunity

NK cells were characterized by their ability to spontaneously kill certain tumor and virus-infected cells. They constitute first line of defense against invading pathogens and usually become activated in viral infections particularly in early phases. Activated NK cells play a crucial role in the induction and amplification of virus-specific immunity by providing IFN-gamma and "danger signal". The functional activities of NK cells are regulated by a balance between the engagement of their inhibitory and activating receptors. In recent years, the discovery of several MHC and non-MHC binding NK receptors has provided important insights regarding NK cell biology and its role in viral infections. These receptors are increasingly being viewed as important regulators of immune response. Like many other viruses, HIV also seems to activate NK cells. However, several studies have reported compromised NK cell functions in HIV-infected individuals. The virus employs several strategies to counter the host's NK cell response, e.g., a differential downregulation of MHC class I molecules on the surface of infected cells, a dysregulated production of NK cell function-enhancing cytokines, direct inhibitory effects of certain viral proteins on NK cell functions, and changes in the expression of NK cell receptors, etc. The individuals expressing activating NK cell receptors and their cognate MHC ligands have activated NK cells. The development of AIDS is significantly delayed in these individuals after HIV infection. The discovery of NK receptors and their ligands has opened new avenues of developing AIDS vaccine and boosting innate and adaptive antiviral immunity in HIV-infected individuals.     

VE1 immunohistochemistry is an adjunct tool for detection of BRAF V600E mutation: Validation in thyroid cancer patients

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy among other endocrine tumors, and BRAF ^V600E is a frequent genetic mutation occurring in the disease. Although different molecular techniques, most importantly sequencing has been widely recognized as a gold standard but molecular diagnosis remains an expensive, laborious, and time‐intensive process. Recently, immunohistochemistry (IHC) with anti‐BRAF V600E (VE1) antibody has increased practical utility and implemented clinically for the detection of BRAF ^V600E mutation. Therefore, the study aimed to evaluate diagnostic accuracy of VE1 IHC for detecting the BRAF ^V600E mutation frequency and clinical implementation in diagnostic laboratories. In this study, 72 formalin fixed paraffin‐embedded tissues (FFPE) were used to determine the BRAF ^V600E mutation status using IHC and Sanger sequencing. The mutation was found in 29% and 28% cases using IHC and Sanger sequencing, respectively. Furthermore, the results showed 100% sensitivity, 98.07% specificity, 95.2% positive predictive value, and 100% negative predictive value. Notably, significant associations were found between BRAF ^V600E status and tumor stage, tumor focality, and extrathyroidal extensions, respectively. VE1 IHC was found to be a highly sensitive, specific, and diagnostically accurate method in this cohort. Therefore, BRAF ^V600E detection through IHC has been considered as the best tailored technique for routine pathology laboratories.     

Identification of novel markers for mouse CD4+ T follicular helper cells

CD4⁺ T follicular helper (T_FH) cells are central for generation of long‐term B‐cell immunity. A defining phenotypic attribute of T_FH cells is the expression of the chemokine R CXCR5, and T_FH cells are typically identified by co‐expression of CXCR5 together with other markers such as PD‐1, ICOS, and Bcl‐6. Herein, we report high‐level expression of the nutrient transporter folate R 4 (FR4) on T_FH cells in acute viral infection. Distinct from the expression profile of conventional T_FH markers, FR4 was highly expressed by naive CD4⁺ T cells, was downregulated after activation and subsequently re‐expressed on T_FH cells. Furthermore, FR4 expression was maintained, albeit at lower levels, on memory T_FH cells. Comparative gene expression profiling of FR4^hi versus FR4^lo Ag‐specific CD4⁺ effector T cells revealed a molecular signature consistent with T_FH and T_H1 subsets, respectively. Interestingly, genes involved in the purine metabolic pathway, including the ecto‐enzyme CD73, were enriched in T_FH cells compared with T_H1 cells, and phenotypic analysis confirmed expression of CD73 on T_FH cells. As there is now considerable interest in developing vaccines that would induce optimal T_FH cell responses, the identification of two novel cell surface markers should be useful in characterization and identification of T_FH cells following vaccination and infection.     

The clinical effectiveness of reconstructing 18F-sodium fluoride PET/CT bone using Bayesian penalized likelihood algorithm for evaluation of metastatic bone disease in obese patients

Objective:A new Bayesian penalized likelihood reconstruction algorithm for positron emission tomography (PET) (Q.Clear) is now in clinical use for fludeoxyglucose (FDG) PET/CT. However, experience with non-FDG tracers and in special patient populations is limited. This pilot study aims to compare Q.Clear to standard PET reconstructions for ¹⁸F sodium fluoride (¹⁸F-NaF) PET in obese patients.Methods:30 whole body ¹⁸F-NaF PET/CT scans (10 patients with BMI 30–40 Kg/m² and 20 patients with BMI >40 Kg/m²) and a NEMA image quality phantom scans were analyzed using ordered subset expectation maximization (OSEM) and Q.Clear reconstructions methods with B400, 600, 800 and 1000. The images were assessed for overall image quality (IQ), noise level, background soft tissue, and lesion detectability, contrast recovery (CR), background variability (BV) and contrast-to-noise ratio (CNR) for both algorithms.Results:CNR for clinical cases was higher for Q.Clear than OSEM (p < 0.05). Mean CNR for OSEM was (21.62 ± 8.9), and for Q.Clear B400 (31.82 ± 14.6), B600 (35.54 ± 14.9), B800 (39.81 ± 16.1), and B1000 (40.9 ± 17.8). As the β value increased the CNR increased in all clinical cases. B600 was the preferred β value for reconstruction in obese patients. The phantom study showed Q.Clear reconstructions gave lower CR and lower BV than OSEM. The CNR for all spheres was significantly higher for Q.Clear (independent of β) than OSEM (p < 0.05), suggesting superiority of Q.Clear.Conclusion:This pilot clinical study shows that Q.Clear reconstruction algorithm improves overall IQ of ¹⁸F-NaF PET in obese patients. Our clinical and phantom measurement results demonstrate improved CNR and reduced BV when using Q.Clear. A β value of 600 is preferred for reconstructing ¹⁸F-NaF PET/CT with Q.Clear in obese patients.Advances in knowledge:¹⁸F-NaF PET/CT is less susceptible to artifacts induced by body habitus. Bayesian penalized likelihood reconstruction with¹⁸F-NaF PET improves overall IQ in obese patients.     

A review of staging chest CT in trunk and extremity soft tissue sarcoma

Objectives:To determine the incidence of pulmonary metastases on chest CT in trunk and extremity soft tissue sarcoma based on two size criteria, and to identify factors associated with metastases.Methods:Retrospective review of chest CT studies in patients with trunk and extremity soft tissue sarcoma over an 18-month period. Data collected included patient age/sex, tumour location, size and relationship to fascia. All chest CTs were reviewed for the presence of metastases which were diagnosed according to two size criteria: multiple nodules > 5 mm in size or multiple nodules > 10 mm in size. Follow-up CT studies were reviewed in cases initially considered indeterminate.Results:127 males and 73 females were included (mean age 57.1 years; range 10–90 years). 147 (73.5%) tumours were deep to the fascia and 53 (26.5%) superficial. Tumour size classified according to the 12 AJCC 2019 criteria was: T1 = 52, T2 = 76, T3 = 39, T4 = 33. Based on nodule size >5 mm, 73 (36.5%) patients had no metastases, 42 (21%) had metastases, while 85 (42.5%) studies were indeterminate. Based on nodule size >10 mm, 73 (36.5%) patients had no metastases, 28 (14%) had metastases, while 99 (49.5%) studies were indeterminate. Larger maximum dimension of the primary tumour was a risk factor for pulmonary metastases using both size criteria.Conclusion:The incidence of pulmonary metastases at presentation in trunk and extremity soft tissue sarcoma is 14–21%. 42.5–49.5% of chest CTs were indeterminate.Advances in knowledge:The incidence of pulmonary metastases at presentation in trunk and extremity soft tissue sarcoma is 14–21%. Indeterminate pulmonary nodules are also very common.     

Pictorial review: imaging of the spinal manifestations of achondroplasia

Achondroplasia is the commonest hereditary skeletal dysplasia exhibiting dwarfism with characteristic rhizomelic (proximal) shortening of the limbs. It is predominantly linked with an autosomal dominant inheritance, but sporadic mutations can occur which are associated with advanced maternal age. Approximately 1 in every 25 000–30 000 live births are affected, and the overall life expectancy is marginally reduced by ~10 years. Mutations in the fibroblast growth factor receptor causes a decrease in endochondral ossification, which results in stunted growth of cartilaginous bones. A resultant narrowed foramen magnum and a short clivus are seen which predisposes to craniocervical spinal canal stenosis. Apnoeic events arising from the compression of the vertebral arteries at the level of the craniocervical junction lead to fatality in the young, with a death rate as high as 7.5%. Decrease in the caudal inter-pedicular distance is characteristic and a contributory factor for cervical, thoracic and lumbar spinal canal stenosis, most pronounced in the lumbar spine with patients often requiring surgical intervention to ease symptoms. Thoracolumbar kyphoscoliosis and sacral manifestations such as small sacro-sciatic notches and a horizontal pelvis are seen. The aim of this pictorial review is to demonstrate the imaging findings of the spinal and pelvic manifestations of achondroplasia.