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Background Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4 + T cell, and CD8 + T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE). Methods We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. Results From 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8 + and 284 CD4 + T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides. Conclusions Overall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-β1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-β1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-β1 signaling axis.

Non-small cell lung cancer (NSCLC) largely consists of lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD). Alterations in the tumor protein p53 (TP53) and phosphatase and tensin homolog (PTEN) tumor suppressors are common in both subtypes, but their relationship with SOX2 is poorly understood. We deleted Trp53 or Pten in a C57BL/6 Sox2hi Nkx2-1-/- Lkb1-/- (SNL) genetic background and generated a highly metastatic LUSC cell line (LN2A; derived from a Sox2hi mouse model, followed by Trp53, Pten, and cyclin dependent kinase inhibitor 2A [Cdkn2a] deletion). Histologic and single-cell RNA-Seq analyses corroborated that SNL mice developed mixed tumors with both LUAD and LUSC histopathology while SNL-Trp53 and SNL-Pten mice developed LUAD and LN2A tumors that retained LUSC morphology. Compared with SNL mice, additional loss of Trp53 or Pten resulted in significantly reduced survival, increased tumor burden, and altered tumor mucin composition. We identified a subcluster of CD38+ tumor-associated inflammatory monocytes in the LN2A model that was significantly enriched for activation of the classical and alternative complement pathways. Complement factor B (CFB) is associated with poor survival in patients with LUSC, and we observed the LN2A model had significantly improved survival on a Cfb-/- background. Our findings demonstrate a cooperative role of Trp53 and Pten tumor suppressors in Sox2-mediated NSCLC tumor progression, mucin production, and remodeling of the immune tumor microenvironment.

Alcohol use is a key risk factor for HIV infection among MSM, in part because intoxication may interfere with the use of prevention methods like condoms. However, few studies have examined whether this is due to alcohol’s pharmacological or expectancy effects or explored the specific aspects of sexual decision-making that may be affected. In this study, high-risk, heavy drinking MSM (N = 121) were randomly assigned to receive either (1) alcohol beverages, (2) placebo beverages, or (3) control beverages, before navigating a video-based sexual risk scenario that assessed several aspects of sexual decision-making. Results showed that condom use intentions and negotiation behaviors were lower among alcohol and placebo participants compared with controls, but that few significant differences emerged between the alcohol and placebo groups. These findings contrast with similar past studies, and suggest that alcohol’s expectancy effects may play a role in sexual decision-making.

Men who have sex with men (MSM) continue to be at especially high risk for HIV in the United States. Past studies have shown that rates of HIV testing differ across a number of demographic and behavioral factors, and this research may be helpful for targeting efforts to increase testing among certain subgroups of MSM. In this study, MSM were recruited from several online sources to complete a questionnaire on HIV testing. Generalized ordered logit models suggested that the odds of having tested within the last 12 months were higher among racial/ethnic minority MSM, those with a college degree, and those who engaged in more recent HIV-risk behavior. The odds of having tested within the last 12 months were also higher among those who reported having sex with a partner they met online in the last 12 months. Conversely, the odds of having tested in the last 12 months were lower among those who reported drinking alcohol heavily, when compared with more moderate drinkers, highlighting yet another potential impact of alcohol on HIV outcomes.

Malignant pleural effusion (MPE) is a serious complication occurring when cancer cells are found in the pleural cavity surrounding the lung. MPE is typically associated with highly metastatic disease caused by primary tumors from non-pleural tissues, but can also arise directly from cancerous transformation within the pleural lining, as seen in malignant pleural mesotheliomas. 15% of cancer patients will develop MPEs, which are associated with a dismal median survival of 3-12 months. Thus, it is imperative that efforts are made to understand the complex factors driving MPE pathophysiology. This thesis will discuss aspects currently known – and identify knowledge gaps regarding – cancer cell intrinsic MPE biology and heterotypic interactions within the tumor and immunologic pleural ecosystem. Furthermore, clinical opportunities of studying MPE will be discussed, identifying promising directions for MPE research that may result in improved disease understanding, ultimately aiming to improve clinical outcomes for these patients with advanced cancer.

Background: The incidence of Hashimoto thyroiditis as well as Graves disease in patients with thyroid cancer has been observed however molecular and pathophysiological basis of this association has only been hypothesized. Cases of new onset severe thyrotoxicosis and Graves ophthalmopathy shortly after lobectomy for thyroid cancer have not been described to our knowledge. Case: The patient is a 46-year-old woman who had a 2.5cm thyroid nodule. Fine needle aspiration showed atypia of undetermined significance and subsequent thyroid genomic classifier test Thyroseq confirmed positive for fusions involving THADA and IGF2BP3. Since THADA positive nodules are usually associated with low risk thyroid carcinoma and non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid lobectomy was advised. Prior to surgery the patient had positive thyroid peroxidase antibodies and was treated with low dose levothyroxine only during two pregnancies. Surgical pathology confirmed 2.5 cm NIFTP and 2 foci of papillary thyroid microcarcinoma of 0.5mm and 1mm with the background of chronic lymphocytic thyroiditis (Hashimoto). No further therapy was advised. At 6 weeks after left thyroid lobectomy the patient presented for a follow up clinically euthyroid with thyroid stimulating hormone (TSH) of 3 mcIU/mL. Two weeks after this regular follow up visit she started having severe periorbital swelling, double vision and bulging of her eyes that was followed by shortness of breath, palpitations, anxiety, sweating and weight loss. She presented to emergency room and was found to have suppressed TSH and positive TSI and TBII antibodies with high titer. After stabilization of hyperthyroidism with methimazole completion thyroidectomy was performed on patient request. Surgical pathology of the right thyroid lobe showed scattered papillary hyperplasia, chronic inflammation, focal atrophy and lymphoid follicles. Six weeks after completion thyroidectomy the patient is clinically euthyroid on levothyroxine and with significantly improved ophthalmopathy. TSI and TBII antibodies remain positive and continue to downtrend. Conclusion: As partial thyroidectomy for low-risk thyroid carcinoma is becoming increasingly convenient method of therapy we may encounter more surgically triggered autoimmune thyroid disorders in the future.

Objective Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups. Results Precise SNP tracking showed no sample swap errors within the clinical testing laboratories. In contrast, when comparing predicted sex-by-genotype to the provided sex on the test requisition, we identified 110 inconsistencies from 25,015 clinical samples (0.44%), that had occurred during sample collection or accessioning. The genetic sex predictions were confirmed using additional SNP sites in the sequencing data or high-density genotyping arrays. It was determined that discrepancies resulted from clerical errors (49.09%), samples from transgender participants (3.64%) and stem cell or bone marrow transplant patients (7.27%) along with undetermined sample mix-ups (40%) for which sample swaps occurred prior to arrival at genome centers, however the exact cause of the events at the sampling sites resulting in the mix-ups were not able to be determined.

[Full article available at http://rimed.org/rimedicaljournal-2018-04.asp].

For the first time in history, women constitute more than half – 50.7% to be exact – of the United States medical student population.1,2,3 Despite strides made towards gender equality in the student body of medical schools, significant gender disparities remain in various fields of medicine. Disparities are particularly notable in academic medicine and medical leadership. Female physicians are less likely to hold full-time academic medicine positions compared to males, comprising only 37% of these roles.1 Among those who hold full professor positions in academic medicine, only 13% are women.4 Several studies have found that women in academic medicine have lower incomes than their male colleagues, even when adjusted for factors such as age, specialty, education, experience level, and geography.5,6 A 2004 study conducted with 1,814 full-time medical faculty across 24 medical schools in the United States reported that the higher the position in academic medicine that a woman achieved, such as chair specifically, the more substantial the wage gap compared to male counterparts.6,7