Background:Alzheimer’s disease (AD) is currently incurable and a majority of investigational drugs have failed clinical trials. One explanation for this failure may be the invalidity of hypotheses focus-ing on amyloid to explain AD pathogenesis. Recently, hypotheses which are centered on synaptic and met-abolic dysfunction are increasingly implicated in AD.Objective:Evaluate AD hypotheses by comparing neurotransmitter and metabolite marker concentrations in normal versus AD CSF.Methods:Meta-analysis allows for statistical comparison of pooled, existing cerebrospinal fluid (CSF) marker data extracted from multiple publications, to obtain a more reliable estimate of concentrations. This method also provides a unique opportunity to rapidly validate AD hypotheses using the resulting CSF con-centration data. Hubmed, Pubmed and Google Scholar were comprehensively searched for published Eng-lish articles, without date restrictions, for the keywords “AD”, “CSF”, and “human” plus markers selected for synaptic and metabolic pathways. Synaptic markers were acetylcholine, gamma-aminobutyric acid (GABA), glutamine, and glycine. Metabolic markers were glutathione, glucose, lactate, pyruvate, and 8 other amino acids. Only studies that measured markers in AD and controls (Ctl), provided means, standard er-rors/deviation, and subject numbers were included. Data were extracted by six authors and reviewed by two others for accuracy. Data were pooled using ratio of means (RoM of AD/Ctl) and random effects meta-analysis using Cochrane Collaboration’s Review Manager software.Results:Of the 435 identified publications, after exclusion and removal of duplicates, 35 articles were in-cluded comprising a total of 605 AD patients and 585 controls. The following markers of synaptic and met-abolic pathways were significantly changed in AD/controls: acetylcholine (RoM 0.36, 95% CI 0.24-0.53, p<0.00001), GABA (0.74, 0.58-0.94, p<0.01), pyruvate (0.48, 0.24-0.94, p=0.03), glutathione (1.11, 1.01-1.21, p=0.03), alanine (1.10, 0.98-1.23, p=0.09), and lower levels of significance for lactate (1.2, 1.00-1.47, p=0.05). Of note, CSF glucose and glutamate levels in AD were not significantly different than that of the controls.Conclusion:This study provides proof of concept for the use of meta-analysis validation of AD hypothe-ses, specifically via robust evidence for the cholinergic hypothesis of AD. Our data disagree with the other synaptic hypotheses of glutamate excitotoxicity and GABAergic resistance to neurodegeneration, given ob-served unchanged glutamate levels and decreased GABA levels. With regards to metabolic hypotheses, the data supported upregulation of anaerobic glycolysis, pentose phosphate pathway (glutathione), and anaple-rosis of the tricarboxylic acid cycle using glutamate. Future applications of meta-analysis indicate the pos-sibility of further in silico evaluation and generation of novel hypotheses in the AD field.

Interleukin 15 (IL-15) has been evaluated as a potential treatment for solid tumors in clinical trials, but the effectiveness of systemic IL-15 administration as a monotherapy has not been realized. IL-15 receptor alpha (IL-15Rα) can stabilize IL-15 and enhance its bioactivity. The goal of this study was to examine the activity of IL-15/IL-15Rα complex (IL-15cx) to CD8+ T cells and evaluate its potential efficacy in murine breast cancer models. The antitumor efficacy was studied in mouse mammary carcinoma models (Her2/neu transgenic and 4T1-luc mammary cancers) treated with systemic recombinant protein with/without the depletion of myeloid-derived suppressor cells or intra-tumoral gene electrotransfer (GET). IL-15cx shows superior in vivo bioactivity to expand CD8 T cells in comparison to an equimolar single chain IL-15. T-bet is partially involved in CD8 T cell expansion ex vivo and in vivo due to IL-15 or IL-15cx. Intraperitoneal administration of IL-15cx results in a moderate inhibition of breast cancer growth that is associated with an increase in the frequency of cytotoxic CD8 T cells and the improvement of their function. The depletion of myeloid-derived suppressor cells (MDSCs) has no impact on mouse breast cancer growth. IL-15cx treatment diminishes MDSCs in murine tumors. However, it also antagonizes the effects of anti-Gr-1 depleting antibodies. Intratumoral GET with plasmid IL-15/IL-15Rα leads to a long-term survival benefit in 4T1 mammary carcinoma model. An early increase of local cytotoxic cells correlates with GET treatment and an increase of long-term memory T cells results from animals with complete tumor regression. Systemic and local administration of IL-15cx shows two distinct therapeutic responses, a moderate tumor growth inhibition or heterogeneous tumor regressions with survival improvement. Further studies are warranted to improve the efficacy of IL-15cx as an immunotherapy for breast cancer.

Introduction: The presence of fungus in an immunocompetent host is usually disregarded as a mere contaminant, as it can be a commensal organism of the skin, gastrointestinal, urogenital, and respiratory tract. Hence, its growth in cultures has to be interpreted within a clinical context. This case illustrates the challenges experienced when diagnosing Candida parapsilosis necrotizing pneumonia, and the importance for considering candida pneumonia as a differential diagnosis for an immunocompetent patient. After a thorough literature review, we would like to present the first case report of C. parapsilosis causing necrotizing pneumonia in an immunocompetent patient. Case Report: We present a case involving a middle-aged smoking male who presented with respiratory and metabolic abnormalities and was found to have necrotizing pneumonia. He was managed for severe sepsis with lactic acidosis, respiratory failure, and severe acute kidney injury (AKI), which improved with broad spectrum antibiotics and fluids. These conditions improved; however, his respiratory distress did not despite a prolonged course of antibiotics. This led to a workup for other causes of necrotizing pneumonia, after which cultures revealed the growth of C. parapsilosis. He was then started on antifungals and subsequently improved. Conclusion: Candida necrotizing pneumonia is a rare disease for an immune-competent individual; however, chronic lung damage in the setting of a smoking history may make individuals more susceptible. This case illustrates the challenges associated when dealing with such a case, and it is the team’s hope that publishing this case will add to awareness. Additionally, this can contribute to improved antibiotic stewardship and earlier diagnosis which will hopefully lead to a shorter hospital stay and improved morbidity and mortality.

Systemic sclerosis (SSc) is a chronic autoimmune disease, characterized by immune system dysregulation, uncontrolled deposition of collagen and microvascular damage in the skin and several internal organs. T cells have a key role in the initiation and propagation of SSc. Our laboratory has previously identified the presence of high proportions of identical α- and β-chains TCR transcripts in skin biopsies from patients with SSc of recent onset, demonstrating clonal expansion of T cells in response to one or more antigens. In order to identify these antigens, pairs of those in vivo clonally expanded α- and β-chain TCR transcripts from two patients with SSc (SSc-21 and SSc-22) were expressed in mutant TCR negative T cells, J.RT3-T3.5, generating a total of 52 T cell lines, including 10 controls. An intracellular Ca2+ mobilization assay was employed to examine whether these transduced Jurkat T cell lines recognize putative SSc antigens presented by autologous EBV-transformed B cell lines. The self-antigen, DNA topoisomerase I and CMV and parvovirus antigens were tested. Statistically significant intracellular Ca2+ mobilization was observed in response to 3 DNA topoisomerase I and 2 CMV peptides by 5 T cell lines expressing clonally expanded α- and β-chain TCR transcripts from patient SSc-21 and SSc-22. These results demonstrate that clonally expanded T cells recognizing DNA topoisomerase I or CMV antigens are present in skin biopsies of recent onset of patients with SSc.

An electrical engineering technology, nanosecond electric pulse (nsEP), has been studied to ablate local tumor in a non-thermal and minimally invasive manner. Recently, several groups including our lab discovered that animals with complete tumor ablation following nsEP treatment were protected from a second tumor challenge. Therefore, nsEP tumor ablation is also a novel in situ vaccination approach. Breast cancer is considered a low immunogenic tumor with only a small subset of patients responsive to immune checkpoint inhibitors. We found nsEP treatment resulted in not only a potent in situ vaccine effect in a poorly immunogenic 4T1 mouse breast cancer model but also an abscopal effect, a rejection of distant untreated tumor lesion. We further examined the impact of nsEP on cancer cell death, tumor microenvironment (TME) modification, the dynamic changes of local and systemic immune response. 4T1 cells treated with nsEP did not show apoptotic death markers but released damage-associated molecular patterns, including calreticulin, high mobility group protein B1, and ATP. In contrast to abundant immune suppressor cells in untreated breast TME, nsEP treatment led to a significant reduction of both myeloid-derived suppressor cells and regulatory T cells. Conversely, the ratio of tumor associated macrophages M1-like verse M2-like was reversed. An increase of tissue-resident memory T cells was observed in draining lymph nodes. In summary, our results suggest that nsEP is a novel non-drug immunogenic cell death inducer and in situ vaccination approach. Further elucidation of its mechanisms and the development of an in vivo nsEP delivery system suitable for patients is critical to warrant this novel technology toward a clinical trial.