Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy.

Recent large scale genomic studies from the Clinical Lung Cancer Genome Project have identified different driver gene mutations in the subtypes of non-small cell lung carcinoma (NSCLC). These findings not only lead to remarkable progress in targeted therapies for lung cancer patients, but also provide fundamental knowledge for the subclassification of NSCLC. More recently, the advancement and clinical application of immunotherapy have reinforced the need for the accurate subclassification of NSCLC. In 2015, the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) updated their guidelines for the subclassification of lung cancers. These guidelines emphasize: (1) the subclassification of NSCLC, (2) the critical role of molecular characterization of tumors for targeted therapy, (3) the unique terminology for subclassifying NSCLC using small biopsy specimens, and (4) the utility of IHC biomarkers in the accurate diagnosis and subclassification of lung cancer. The guidelines have significant prognostic impact on oncologic practice and patient care. In this review, we summarize the current WHO guidelines for the classification of lung cancer, discuss advancements of targeted therapy and immunotherapy, and address the utility and limitation of immunomarkers in the subclassification of NSCLC, as well as the prospective future of the field.

Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma.

Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) have been implicated as drivers of tumor progression across a variety of cancers. Recent evidence suggests MIF as a therapeutic target in immune checkpoint inhibition (ICI) resistant melanomas, however clinical evidence of MIF and particularly of DDT remain limited. This retrospective study analyzed 97 patients treated at Yale for melanoma between 2002-2020. Bulk-RNA sequencing of patient tumor samples from the Skin Cancer SPORE Biorepository was used to evaluate for differential gene expression of MIF, DDT, CD74, and selected inflammatory markers, and gene expression was correlated with patient survival outcomes. Our findings revealed a strong correlation between MIF and DDT levels, with no statistically significant difference across common melanoma mutations and subtypes. Improved survival was associated with lower MIF and DDT levels and higher CD74:MIF and CD74:DDT levels. High CD74:DDT and CD74:MIF levels were also associated with enrichment of infiltrating inflammatory cell markers. These data suggest DDT as a novel target in immune therapy. Dual MIF and DDT blockade may provide synergistic responses in patients with melanoma, irrespective of common mutations, and may overcome ICI resistance. These markers may also provide prognostic value for further biomarker development.

COMBREX: a project to accelerate the functional annotation of prokaryotic genomes.

COMBREX (http://combrex.bu.edu) is a project to increase the speed of the functional annotation of new bacterial and archaeal genomes. It consists of a database of functional predictions produced by computational biologists and a mechanism for experimental biochemists to bid for the validation of those predictions. Small grants are available to support successful bids.

Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

CD45RA+ effector memory (EM) CD8+ T cell expansion was reported in Alzheimer's disease (AD). Such cells are IL-7 receptor alpha (IL-7Rα)low EM CD8+ T cells, which expand with age and have a unique aging gene signature (i.e., IL-7Rαlow aging genes). Here we investigated whether IL-7Rαlow aging genes and previously reported AD and memory (ADM) genes overlapped with clinical significance in AD patients. RT-qPCR analysis of 40 genes, including 29 ADM, 9 top IL-7Ralow aging and 2 control genes, showed 8 differentially expressed genes between AD and cognitively normal groups; five (62.5%) of which were top IL-7Rαlow aging genes. Over-representation analysis revealed that these genes were highly present in molecular and biological pathways associated with AD. Distinct expression levels of these genes were associated with neuropsychological testing performance in 3 subgroups of dementia participants. Our findings support the possible implication of the IL-7Rαlow aging gene signature with AD.

Ultrasound-Guided Transthoracic Fine-Needle Aspiration: A Reliable Tool in Diagnosis and Molecular Profiling of Lung Masses.

INTRODUCTION: Pulmonary adenocarcinoma is a major cause of mortality worldwide. The majority of patients present with advanced stage disease, and minimally invasive procedures are desirable for diagnosis and treatment plans. Herein, we report our experience with percutaneous/transthoracic needle aspiration (TT-NA) in the cytologic diagnosis of pulmonary adenocarcinoma. MATERIAL AND METHODS: After institutional review board approval, the cytopathology electronic data system was searched for all consecutive TT-NA of the lung masses from January 2011 to November 2015. Patients' medical records were reviewed and cytologic materials were evaluated. RESULTS: A total of 151 specimens were identified, with a mean age of 62.8 years; 62.9% of the patients had a prior history of malignancy. Carcinoma/adenocarcinoma was the most common (80%) diagnosis. The targeted lesions were predominantly located in the lung (56.3%, 81/151) and pleural based (27.8%, 42/151). The mean size of the lesions was 3.6 cm. Cytology specimens were adequate in 70.9% of the cases, while 72.8% (110/151) of the cases also had concurrent core biopsy. A malignant diagnosis was rendered in the majority of the cases (64.9%). In 71% of the cases, immunohistochemistry/histochemistry studies were successfully performed. Molecular/genetic studies were requested in 80% of the cases and had adequate material. Complications of the procedure were seen in 9.9% of the patients including pneumothorax (7.9%) and hemoptysis (1.9%). CONCLUSION: TT-NA is a relatively safe and reliable technique in the assessment of pulmonary lesions.

Current insight in the localized insulin-derived amyloidosis (LIDA): clinico-pathological characteristics and differential diagnosis.

BACKGROUND: In diabetic patients, subcutaneous insulin injection may cause several types of injection site-related lesions, such as lipoatrophy, insulin-induced cutaneous lipohypertrophy (IICL), allergic reaction, and iatrogenic localized insulin-derived amyloidosis (LIDA). Among these complications, both IICL and LIDA present as tumor-like and slow growing lesions; and they may be confused with one another. The clinical implication and management of IICL and LIDA are different. LIDA causes poor blood glycemic controls due to inadequate absorption of the insulin. Thus, accurate diagnosis of the lesion is critical in diabetic patients. REVIEW OF LITERATURE: LIDA is an extremely rare complication and often overlooked, it is managed by a surgical intervention. Whereas, IICL is a common side effect and can be managed by a non-surgical approach. Furthermore, in long-standing diabetics, patients may develop hypertrophic cardiomyopathy, proteinuria, peripheral, and autonomic neuropathy; these symptoms can be mistaken for a systemic amyloidosis. It is also necessary to distinguish LIDA from the systemic amyloidosis, which requires a more aggressive systemic therapy. LIDA should also be distinguished from primary cutaneous amyloidosis, with high risk of progression to a systemic amyloidosis. In this effort we reviewed 25 published manuscripts, including case reports and case series studies. We also summarized the literature and discussed differential diagnosis, including the approach to diagnose LIDA. CONCLUSION: The identification of amyloid material and immunoreactivity with anti-insulin antibodies are key diagnostic features of LIDA. Although several clinical and animal studies were made in recent years, the lesion is still under-diagnosed and underreported. The clinical suspicion and knowledge of the lesion play a crucial role for the accurate diagnosis of LIDA. Surgical excision of the lesion can dramatically decrease insulin requirement and improve glycemic control.

Thousands of missed genes found in bacterial genomes and their analysis with COMBREX.

BACKGROUND: The dramatic reduction in the cost of sequencing has allowed many researchers to join in the effort of sequencing and annotating prokaryotic genomes. Annotation methods vary considerably and may fail to identify some genes. Here we draw attention to a large number of likely genes missing from annotations using common tools such as Glimmer and BLAST. RESULTS: By analyzing 1,474 prokaryotic genome annotations in GenBank, we identify 13,602 likely missed genes that are homologs to non-hypothetical proteins, and 11,792 likely missed genes that are homologs only to hypothetical proteins, yet have supporting evidence of their protein-coding nature from COMBREX, a newly created gene function database. We also estimate the likelihood that each potential missing gene found is a genuine protein-coding gene using COMBREX. CONCLUSIONS: Our analysis of the causes of missed genes suggests that larger annotation centers tend to produce annotations with fewer missed genes than smaller centers, and many of the missed genes are short genes <300 bp. Over 1,000 of the likely missed genes could be associated with phenotype information available in COMBREX. 359 of these genes, found in pathogenic organisms, may be potential targets for pharmaceutical research. The newly identified genes are available on COMBREX's website. REVIEWERS: This article was reviewed by Daniel Haft, Arcady Mushegian, and M. Pilar Francino (nominated by David Ardell).