Cardiac metastasis from a squamous cell carcinoma of the tongue presenting with symptoms of endocarditis: a case report.

Cardiac metastasis of squamous cell carcinoma (SCC) of the tongue is rare. This report presents a known case of SCC of the tongue in a patient who was admitted with an initial diagnosis of pneumonia and endocarditis and had received wide spectrum antibiotics. Due to the lack of an appropriate response, surgical valve replacement was initially considered, but further evaluation by cardiac MRI revealed multiple cardiac, lung and paravertebral metastases, most probably from the previous SCC and as such the patient was managed conservatively. This case report highlights the importance of cardiac MRI for evaluating head and neck tumors and choosing optimal treatment plans.

Mouth cancer (also known as oral squamous cell carcinoma can spread to other areas of the body, including the heart ­ this is referred to as cardiac metastases. Although cardiac metastases is rare, it can change the surgical plan and prognosis of the disease. A young woman with a prior history of tongue squamous cell carcinoma was admitted with what was believed to be an infection of the inner surface of the heart, this is also known as infective endocarditis. However, a technique used to assess the function and structure of the cardiovascular system inside the heart called cardiac MRI, showed that the cancer had spread to multiple areas of the heart. With this knowledge the patient was managed conservatively but passed away 1 month later.

Antibodies induced by an ancestral SARS-CoV-2 strain that cross-neutralize variants from Alpha to Omicron BA.1.

Neutralizing antibodies that recognize the SARS-CoV-2 spike glycoprotein are the principal host defense against viral invasion. Variants of SARS-CoV-2 bear mutations that allow escape from neutralization by many human antibodies, especially those in widely distributed ("public") classes. Identifying antibodies that neutralize these variants of concern and determining their prevalence are important goals for understanding immune protection. To determine the Delta and Omicron BA.1 variant specificity of B cell repertoires established by an initial Wuhan strain infection, we measured neutralization potencies of 73 antibodies from an unbiased survey of the early memory B cell response. Antibodies recognizing each of three previously defined epitopic regions on the spike receptor binding domain (RBD) varied in neutralization potency and variant-escape resistance. The ACE2 binding surface ("RBD-2") harbored the binding sites of neutralizing antibodies with the highest potency but with the greatest sensitivity to viral escape; two other epitopic regions on the RBD ("RBD-1" and "RBD-3") bound antibodies of more modest potency but greater breadth. The structures of several Fab:spike complexes that neutralized all five variants of concern tested, including one Fab each from the RBD-1, -2, and -3 clusters, illustrated the determinants of broad neutralization and showed that B cell repertoires can have specificities that avoid immune escape driven by public antibodies. The structure of the RBD-2 binding, broad neutralizer shows why it retains neutralizing activity for Omicron BA.1, unlike most others in the same public class. Our results correlate with real-world data on vaccine efficacy, which indicate mitigation of disease caused by Omicron BA.1.

HLA class I antigen processing machinery defects in antitumor immunity and immunotherapy.

Human leukocyte antigen (HLA) class I antigen-processing machinery (APM) plays a crucial role in the synthesis and expression of HLA class I tumor antigen-derived peptide complexes; the latter mediate the recognition and elimination of malignant cells by cognate T cells. Defects in HLA class I APM component expression and/or function are frequently found in cancer cells, providing them with an immune escape mechanism that has relevance in the clinical course of the disease and in the response to T-cell-based immunotherapy. The majority of HLA class I APM defects (>75%) are caused by epigenetic mechanisms or dysregulated signaling and therefore can be corrected by strategies that counteract the underlying mechanisms. Their application in oncology is likely to improve responses to T-cell-based immunotherapies, including checkpoint inhibition.

CAR T Cell-Based Immunotherapy for the Treatment of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.

A Precision Medicine Drug Discovery Pipeline Identifies Combined CDK2 and 9 Inhibition as a Novel Therapeutic Strategy in Colorectal Cancer.

Colorectal cancer is the third most common cancer in the United States and responsible for over 50,000 deaths each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new treatments for this deadly disease. To address this need, we developed a precision medicine pipeline that integrates high-throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDX) to identify new treatments for colorectal cancer. High-throughput screens of 2,100 compounds were performed across six low-passage, patient-derived colorectal cancer cell lines. These screens identified the CDK inhibitor drug class among the most effective cytotoxic compounds across six colorectal cancer lines. Among this class, combined targeting of CDK1, 2, and 9 was the most effective, with IC50s ranging from 110 nmol/L to 1.2 µmol/L. Knockdown of CDK9 in the presence of a CDK2 inhibitor (CVT-313) showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Mechanistically, dual CDK2/9 inhibition induced significant G2-M arrest and anaphase catastrophe. Combined CDK2/9 inhibition in vivo synergistically reduced PDX tumor growth. Our precision medicine pipeline provides a robust screening and validation platform to identify promising new cancer therapies. Application of this platform to colorectal cancer pinpointed CDK2/9 dual inhibition as a novel combinatorial therapy to treat colorectal cancer.

Aloe Vera Gel-derived Eye Drops for Alkaline Corneal Injury in a Rabbit Model.

PURPOSE: To investigate the efficacy of topical Aloe Vera (AV) gel-derived eye drops on the healing of alkali-burned corneas in rabbits. METHODS: Thirty alkali-burned corneas of 30 New Zealand albino rabbits were categorized into three groups: AV treatment group that received AV gel-derived eye drops four times a day; medical therapy (MT) group that received conventional treatment; and the control group. Clinical examinations together with digital imaging of the corneas were performed on days 0, 1, 2, 4, and 7. The area of the corneal epithelial defect (CED) was measured using ImageJ software. After euthanizing the rabbits, the affected corneas were evaluated by histopathological examination. Finally, the clinical and histopathological results were compared among the groups. RESULTS: The CED area on days 2 and 7 was significantly less in the AV group than that in the MT group (P = 0.007 and P = 0.024, respectively) and the control group (P = 0.003 and P = 0.037, respectively). None of the cases developed hypersensitivity reactions, limbal ischemia, descemetocele, or corneal perforation during the study period. Based on histopathology, the AV group had notably less keratocyte loss than the MT group (P = 0.001) and the control group (P = 0.022). The inflammatory response after the alkali burn was higher in the AV group than that in the controls (P = 0.028). CONCLUSION: Short-term topical AV treatment was effective in healing alkali-burned corneas and hastened corneal re-epithelialization as compared to MT; however, AV gel-derived eye drops did not reduce the inflammatory response.

Meta-analysis of GABRB3 Gene Polymorphisms and Susceptibility to Autism Spectrum Disorder.

Several lines of evidence have suggested that the GABA receptor subunit ß3 (GABRB3) gene is a genetic contributor in the autism spectrum disorder (ASD). The aberrant expression of GABRB3 is reported in ASD patients which may be a consequence of the presence of certain genetic variants in the promoter region of the gene. The associations between single-nucleotide polymorphisms (SNPs) within this gene and ASD have been analyzed in previous studies. However, the results are conflicting. In the present study, we performed a meta-analysis on association between two SNPs located in the promoter region of GABRB3 gene (rs4906902 and rs20317) and ASD. The literature search was performed based on criteria provided by the meta-analysis of observational studies in epidemiology (MOOSE). The association between mentioned SNPs and ASD was calculated using pooled odd ratios (ORs) and 95% confidence intervals. The result of the present meta-analysis indicates that neither rs4906902 nor rs20317 are significantly associated with the risk of ASD. The underlying mechanism of the aberrant expression of GABRB3 gene in ASD patients should be investigated in other biological levels.

Anterior Spinal Artery Syndrome Following Coronary Artery Bypass Grafting: a Case Report.

We present a patient with unstable angina candidate for coronary artery bypass grafting. Saphenous vein graft was used in obtuse marginal and left internal mammary artery to left anterior descending artery properly. After surgery, the patient experienced flaccid paralysis of lower limb and impaired sensation of touch and warmth of knee and below. A computed tomography angiogram of lower limbs and thoracolumbar magnetic resonance imaging showed no abnormality. Based on the symptom, clinical diagnosis of anterior spinal artery syndrome was considered. The artery of Adamkiewicz is an important supplier to the anterior spinal artery. Internal thoracic mammary artery, used in coronary artery bypass grafting, is suspected as a collateral supplier of the artery of Adamkiewicz and has been accused for cause of spinal infarction.

Anterior spinal artery syndrome following coronary artery bypass grafting: a case report

Abstract We present a patient with unstable angina candidate for coronary artery bypass grafting. Saphenous vein graft was used in obtuse marginal and left internal mammary artery to left anterior descending artery properly. After surgery, the patient experienced flaccid paralysis of lower limb and impaired sensation of touch and warmth of knee and below. A computed tomography angiogram of lower limbs and thoracolumbar magnetic resonance imaging showed no abnormality. Based on the symptom, clinical diagnosis of anterior spinal artery syndrome was considered. The artery of Adamkiewicz is an important supplier to the anterior spinal artery. Internal thoracic mammary artery, used in coronary artery bypass grafting, is suspected as a collateral supplier of the artery of Adamkiewicz and has been accused for cause of spinal infarction.

Long-term survival of a small cell lung cancer patient with proper endobronchial management.

Small cell lung cancer (SCLC) is considered as a disease with poor prognosis and early metastasis with a very short survival. Endobronchial involvement is fairly common finding in SCLC and can cause respiratory symptoms. In this report we present a 47-year-old man diagnosed with small cell lung cancer. In the disease course, primary involvement of right bronchus spread to left bronchus and carina. Scheduled sessions of bronchoscopic interventions with electrocautery and argon plasma coagulation were used to maintain his large airways open. The intrabronchial interventions were accompanied by six courses of cisplatin-based chemotherapy as a standard treatment. Although patient's definite diagnosis was extensive SCLC, he remained in a good condition for 5 years. In last year of his follow up, headache and dizziness were added to his occasional respiratory symptoms. Brain MRI identified metastatic lesion in his brain. Hence, brain radiotherapy was suggested, but he refused further aggressive treatment. Seven months later, he died of brain metastatic lesion. Considering long survival of this patient with adequate and proper scheduled endobronchial interventions along with standard courses of chemotherapy, we conclude that this combined treatment strategy in patients with endobronchial involvement might increase survival.