Tumor microenvironmental determinants of high-risk DCIS progression.

Ductal carcinoma in situ (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent invasive carcinomas at or near the site of biopsy detection. However, only 15-45% of untreated DCIS cases progress to invasive cancer, so understanding mechanisms that prevent progression is key to avoid overtreatment and provides a basis for alternative therapies and prevention. This study was designed to characterize the tumor microenvironment and molecular profile of high-risk DCIS that grew to a large size but remained as DCIS. All patients had DCIS lesions >5cm in size with at least one additional high-risk feature: young age (<45 years), high nuclear grade, hormone receptor negativity, HER2 positivity, the presence of comedonecrosis, or a palpable mass. The tumor immune microenvironment was characterized using multiplex immunofluorescence to identify immune cells and their spatial relationships within the ducts and stroma. Gene copy number analysis and whole exome DNA sequencing identified the mutational burden and driver mutations, and quantitative whole-transcriptome/gene expression analyses were performed. There was no association between the percent of the DCIS genome characterized by copy number variants (CNAs) and recurrence events (DCIS or invasive). Mutations, especially missense mutations, in the breast cancer driver genes PIK3CA and TP53 were common in this high-risk DCIS cohort (47% of evaluated lesions). Tumor infiltrating lymphocyte (TIL) density was higher in DCIS lesions with TP53 mutations (p=0.0079) compared to wildtype lesions, but not in lesions with PIK3CA mutations (p=0.44). Immune infiltrates were negatively associated with hormone receptor status and positively associated with HER2 expression. High levels of CD3+CD8- T cells were associated with good outcomes with respect to any subsequent recurrence (DCIS or invasive cancer), whereas high levels of CD3+Foxp3+ Treg cells were associated with poor outcomes. Spatial proximity analyses of immune cells and tumor cells demonstrated that close proximity of T cells with tumor cells was associated with good outcomes with respect to any recurrence as well as invasive recurrences. Interestingly, we found that myoepithelial continuity (distance between myoepithelial cells surrounding the involved ducts) was significantly lower in DCIS lesions compared to normal tissue (p=0.0002) or to atypical ductal hyperplasia (p=0.011). Gene set enrichment analysis identified several immune pathways associated with low myoepithelial continuity and a low myoepithelial continuity score was associated with better outcomes, suggesting that gaps in the myoepithelial layer may allow access/interactions between immune infiltrates and tumor cells. Our study demonstrates the immune microenvironment of DCIS, in particular the spatial proximity of tumor cells and T cells, and myoepithelial continuity are important determinants for progression of disease.

IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats.

The enzyme indoleamine 2,3 dioxygenase 1 (IDO1) catalyzes the rate-limiting step in the kynurenine pathway (KP) which produces both neuroprotective and neurotoxic metabolites. Neuroinflammatory signals produced as a result of pathological conditions can increase production of IDO1 and boost its enzymatic capacity. IDO1 and the KP have been implicated in behavioral recovery after human traumatic brain injury (TBI), but their roles in experimental models of TBI are for the most part unknown. We hypothesized there is an increase in KP activity in the fluid percussion injury (FPI) model of TBI, and that administration of an IDO1 inhibitor will improve neurological recovery. In this study, adult male Sprague Dawley rats were subjected to FPI or sham injury and received twice-daily oral administration of the IDO1 inhibitor PF-06840003 (100 mg/kg) or vehicle control. FPI resulted in a significant increase in KP activity, as demonstrated by an increased ratio of kynurenine: tryptophan, in the perilesional neocortex and ipsilateral hippocampus 3 days postinjury (DPI), which normalized by 7 DPI. The increase in KP activity was prevented by PF-06840003. IDO1 inhibition also improved memory performance as assessed in the Barnes maze and anxiety behaviors as assessed in open field testing in the first 28 DPI. These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery.

Chemists Invent Drugs and Drugs Save Lives.

Drug molecules are the centrepiece of modern medical therapies, providing relief from pain, combatting infections and providing a myriad of other therapeutic effects. The quest for new and improved drug molecules drives medical research, and the introduction of a new drug frequently becomes a newsworthy event capturing the attention of the press and general public. And yet, misconceptions abound. Often, the general public thinks that drug molecules are designed, created, and invented by physicians rather than chemists - a misunderstanding that is merely one aspect of a widespread general underappreciation of the role of chemistry in the health and socioeconomic well-being of humankind. Chemistry as a discipline needs to change this narrative. Our journals, conferences, societies, mass media presence and social media postings need to better inform the general public about the societal value of chemistry. Though it is an arduous and time-demanding process, chemists, both in academia and industry, invent the drugs that are advancing medical care. We chemists need to do a better job educating policy makers, politicians, opinion leaders and fundraisers about the valuable contributions of chemistry. We need to have people know what we do, and why we became chemists; we need to engage the general public.

ß-Amyloid Is a Kinocidin Cytokine.

Although ß-amyloid (Aß) has long been studied as a key contributor to the pathology of Alzheimer's disease (AD), its physiological role (if any) remains undetermined. This Viewpoint highlights the evolving concept that if AD is an immunopathic disorder then Aß may be an immunopeptide. The identification of Aß as an immunopeptide is further refined to it being a kinocidin, a subtype of cytokine with antimicrobial activity.

Endogenous Antimicrobial-Immunomodulatory Molecules: Networking Biomolecules of Innate Immunity.

Endogenous antimicrobial-immunomodulatory molecules (EAIMs) are essential to immune-mediated human health and evolution. Conventionally, antimicrobial peptides (AMPs) have been regarded as the dominant endogenous antimicrobial molecule; however, AMPs are not sufficient to account for the full spectrum of antimicrobial-immunomodulatory duality occurring within the human body. The threat posed by pathogenic microbes is pervasive with the capacity for widespread impact across many organ systems and multiple biochemical pathways; accordingly, the host needs the capacity to react with an equally diverse response. This can be attained by having EAIMs that traverse the full range of molecular size (small to large molecules) and structural diversity (including molecules other than peptides). This review identifies multiple molecules (peptide/protein, lipid, carbohydrate, nucleic acid, small organic molecule, and metallic cation) as EAIMs and discusses the possibility of cooperative, additive effects amongst the various EAIM classes during the host response to a microbial assault. This comprehensive consideration of the full molecular diversity of EAIMs enables the conclusion that EAIMs constitute a previously uncatalogued structurally diverse and collectively underappreciated immuno-active group of integrated molecular responders within the innate immune system's first line of defence.

Long-term Mammography Screening Trends and Predictors of Return to Screening after the COVID-19 Pandemic: Results from a Statewide Registry.

Purpose To evaluate long-term trends in mammography screening rates and identify sociodemographic and breast cancer risk characteristics associated with return to screening after the COVID-19 pandemic. Materials and Methods In this retrospective study, statewide screening mammography data of 222 384 female individuals aged 40 years or older (mean age, 58.8 years ± 11.7 [SD]) from the Vermont Breast Cancer Surveillance System were evaluated to generate descriptive statistics and Joinpoint models to characterize screening patterns during 2000-2022. Log-binomial regression models estimated associations of sociodemographic and risk characteristics with post-COVID-19 pandemic return to screening. Results The proportion of female individuals in Vermont aged 50-74 years with a screening mammogram obtained in the previous 2 years declined from a prepandemic level of 61.3% (95% CI: 61.1%, 61.6%) in 2019 to 56.0% (95% CI: 55.7%, 56.3%) in 2021 before rebounding to 60.7% (95% CI: 60.4%, 61.0%) in 2022. Screening adherence in 2022 remained substantially lower than that observed during the 2007-2010 apex of screening adherence (66.1%-67.0%). Joinpoint models estimated an annual percent change of -1.1% (95% CI: -1.5%, -0.8%) during 2010-2022. Among the cohort of 95 644 individuals screened during January 2018-March 2020, the probability of returning to screening during 2020-2022 varied by age (eg, risk ratio [RR] = 0.94 [95% CI: 0.93, 0.95] for age 40-44 vs age 60-64 years), race and ethnicity (RR = 0.84 [95% CI: 0.78, 0.90] for Black vs White individuals), education (RR = 0.84 [95% CI: 0.81, 0.86] for less than high school degree vs college degree), and by 5-year breast cancer risk (RR = 1.06 [95% CI: 1.04, 1.08] for very high vs average risk). Conclusion Despite a rebound to near prepandemic levels, Vermont mammography screening rates have steadily declined since 2010, with certain sociodemographic groups less likely to return to screening after the pandemic. Keywords: Mammography, Breast, Health Policy and Practice, Neoplasms-Primary, Epidemiology, Screening Supplemental material is available for this article. © RSNA, 2024.

Drug Design for Alzheimer's Disease: Biologics vs. Small Molecules.

There shall probably be no "magic bullet" for Alzheimer's; rather, we should be pursuing a "magic shotgun blast" that will target multiple complementary therapeutic receptors. Although protein misfolding/oligomerization will probably be one of these targets, this alone is insufficient and will require the co-administration of other therapeutic entities engaging targets, such as immunopathy, gliopathy, mitochondriopathy, synaptotoxicity or others. Although polypharmacy is emerging as the preferred therapeutic route, many questions remain unanswered. Should this be a cocktail of biologics, a concoction of small molecules, or a judicious combination of both? Biologics and small molecule drugs display both strengths and weaknesses. When addressing a disease as complex and globally important as Alzheimer's, there should be room for the continuing development of both of these therapeutic classes. Each has much to offer, and when used with their advantages and disadvantages in clear focus, an ultimate solution will probably require contributions from both.

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study.

OBJECTIVES: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Multicenter ICU study. PATIENTS: Adults requiring invasive mechanical ventilation secondary to COVID-19. INTERVENTION: Patients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio2 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao2/Fio2 ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control (p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% (p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events. CONCLUSIONS: In this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao2/Fio2 ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology.

Alzheimer's Disease and COVID-19 Pathogenic Overlap: Implications for Drug Repurposing.

As COVID-19 continues, a safe, cost-effective treatment strategy demands continued inquiry. Chronic neuroinflammatory disorders may appear to be of little relevance in this regard; often indolent and progressive disorders characterized by neuroinflammation (such as Alzheimer's disease (AD)) are fundamentally dissimilar in etiology and symptomology to COVID-19's rapid infectivity and pathology. However, the two disorders share extensive pathognomonic features, including at membrane, cytoplasmic, and extracellular levels, culminating in analogous immunogenic destruction of their respective organ parenchyma. We hypothesize that these mechanistic similarities may extent to therapeutic targets, namely that it is conceivable an agent against AD's immunopathy may have efficacy against COVID-19 and vice versa. It is notable that while extensively investigated, no agent has yet demonstrated significant therapeutic efficacy against AD's cognitive and memory declines. Yet this very failure has driven the development of numerous agents with strong mechanistic potential and clinical characteristics. Having already approved for clinical trials, these agents may be an expedient starting point in the urgent search for an effective COVID-19 therapy. Herein, we review the overlapping Alzheimer's/ COVID-19 targets and theorize several initial platforms.

Machine learning classification of diagnostic accuracy in pathologists interpreting breast biopsies.

OBJECTIVE: This study explores the feasibility of using machine learning to predict accurate versus inaccurate diagnoses made by pathologists based on their spatiotemporal viewing behavior when evaluating digital breast biopsy images. MATERIALS AND METHODS: The study gathered data from 140 pathologists of varying experience levels who each reviewed a set of 14 digital whole slide images of breast biopsy tissue. Pathologists' viewing behavior, including zooming and panning actions, was recorded during image evaluation. A total of 30 features were extracted from the viewing behavior data, and 4 machine learning algorithms were used to build classifiers for predicting diagnostic accuracy. RESULTS: The Random Forest classifier demonstrated the best overall performance, achieving a test accuracy of 0.81 and area under the receiver-operator characteristic curve of 0.86. Features related to attention distribution and focus on critical regions of interest were found to be important predictors of diagnostic accuracy. Further including case-level and pathologist-level information incrementally improved classifier performance. DISCUSSION: Results suggest that pathologists' viewing behavior during digital image evaluation can be leveraged to predict diagnostic accuracy, affording automated feedback and decision support systems based on viewing behavior to aid in training and, ultimately, clinical practice. They also carry implications for basic research examining the interplay between perception, thought, and action in diagnostic decision-making. CONCLUSION: The classifiers developed herein have potential applications in training and clinical settings to provide timely feedback and support to pathologists during diagnostic decision-making. Further research could explore the generalizability of these findings to other medical domains and varied levels of expertise.

Multispectral Imaging of Metabolic Fluorophores: Comparing In Vivo and Fresh Ex Vivo Tissue.

The enhanced uptake of glucose by cancer cells via aerobic glycolysis occurs when the lactic acid pathway is favored over the citric acid cycle. The lactic acid cycle in cancer cells influences the cytosolic concentration of metabolic fluorophores including NADH (the reduced form of nicotinamide adenine dinucleotide) and flavin adenine dinucleotide (FAD). In particular, the literature has shown that breast cancer influences the relative magnitude of fluorescence from NADH and FAD. A multispectral imaging system has been developed for rapid non-destructive imaging of intrinsic fluorescence in tissue. This paper compares in vivo data to fresh ex vivo data gathered as a function of time in mouse models. The data indicate that, if measured within 30 min of excision, a cancer diagnosis in fresh ex vivo tissue correlates with a cancer diagnosis in in vivo tissue. These results justify a plan to evaluate fresh ex vivo human tissue to quantify the sensitivity and specificity of the multispectral system.

Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development.

Ductal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations. The somatic mutation topographies revealed that DCIS is multiclonal and consists of spatially discontinuous subclonal lesions. Here we show that this pattern of spread is consistent with a new 'Comet' model of DCIS tumorigenesis, whereby multiple subclones arise early and nucleate the buds of the growing tumor. The discontinuous, multiclonal growth of the Comet model is analogous to the branching morphogenesis of normal breast development that governs the rapid expansion of the mammary epithelium during puberty. The branching morphogenesis-like dynamics of the proposed Comet model diverges from the canonical model of clonal evolution, and better explains observed genomic spatial data. Importantly, the Comet model allows for the clinically relevant scenario of extensive DCIS spread, without being subjected to the selective pressures of subclone competition that promote the emergence of increasingly invasive phenotypes. As such, the normal cell movement inferred during DCIS growth provides a new explanation for the limited risk of progression in DCIS and adds biologic rationale for ongoing clinical efforts to reduce DCIS overtreatment.

Druggable targets for the immunopathy of Alzheimer's disease.

Alzheimer's disease (AD) is one of the leading threats to the health and socioeconomic well-being of humankind. Though research to develop disease modifying therapies for AD has traditionally focussed on the misfolding and aggregation of proteins, this approach has failed to yield a definitively curative agent. Accordingly, the search for additional or alternative approaches is a medicinal chemistry priority. Dysfunction of the brain's neuroimmune-neuroinflammation axis has emerged as a leading contender. Neuroimmunity however is mechanistically complex, rendering the recognition of candidate receptors a challenging task. Herein, a review of the role of neuroimmunity in the biomolecular pathogenesis of AD is presented with the identification of a 'druggable dozen' targets; in turn, each identified target represents one or more discrete receptors centred on a common biochemical mechanism. The druggable dozen is composed of both cellular and molecular messenger targets, with a 'targetable ten' microglial targets as well as two cytokine-based targets. For each target, the underlying molecular basis, with a consideration of strengths and weaknesses, is considered.

Digital mammography and digital breast tomosynthesis for detecting invasive lobular and ductal carcinoma.

PURPOSE: Invasive lobular carcinoma (ILC) is a distinct histological subtype of breast cancer that can make early detection with mammography challenging. We compared imaging performance of digital breast tomosynthesis (DBT) to digital mammography (DM) for diagnoses of ILC, invasive ductal carcinoma (IDC), and invasive mixed carcinoma (IMC) in a screening population. METHODS: We included screening exams (DM; n = 1,715,249 or DBT; n = 414,793) from 2011 to 2018 among 839,801 women in the Breast Cancer Surveillance Consortium. Examinations were followed for one year to ascertain incident ILC, IDC, or IMC. We measured cancer detection rate (CDR) and interval invasive cancer rate/1000 screening examinations for each histological subtype and stratified by breast density and modality. We calculated relative risk (RR) for DM vs. DBT using log-binomial models to adjust for the propensity of receiving DBT vs. DM. RESULTS: Unadjusted CDR per 1000 mammograms of ILC overall was 0.33 (95%CI: 0.30-0.36) for DM; 0.45 (95%CI: 0.39-0.52) for DBT, and for women with dense breasts- 0.33 (95%CI: 0.29-0.37) for DM and 0.54 (95%CI: 0.43-0.66) for DBT. Similar results were noted for IDC and IMC. Adjusted models showed a significantly increased RR for cancer detection with DBT compared to DM among women with dense breasts for all three histologies (RR; 95%CI: ILC 1.53; 1.09-2.14, IDC 1.21; 1.02-1.44, IMC 1.76; 1.30-2.38), but no significant increase among women with non-dense breasts. CONCLUSION: DBT was associated with higher CDR for ILC, IDC, and IMC for women with dense breasts. Early detection of ILC with DBT may improve outcomes for this distinct clinical entity.

Exploring the presence of bovine leukemia virus among breast cancer tumors in a rural state.

PURPOSE: The bovine leukemia virus (BLV) is a deltaretrovirus that causes malignant lymphoma and lymphosarcomas in cattle globally and has high prevalence among large scale U.S. dairy herds. Associations between presence of BLV DNA in human mammary tissue and human breast cancer incidence have been reported. We sought to estimate the prevalence of BLV DNA in breast cancer tissue samples in a rural state with an active dairy industry. METHODS: We purified genomic DNA from 56 fresh-frozen breast cancer tissue samples (51 tumor samples, 5 samples representing adjacent normal breast tissue) banked between 2016 and 2019. Using nested PCR assays, multiple BLV tax sequence primers and primers for the long terminal repeat (LTR) were used to detect BLV DNA in tissue samples and known positive control samples, including the permanently infected fetal lamb kidney cell line (FLK-BLV) and blood from BLV positive cattle. RESULTS: The median age of patients from which samples were obtained at the time of treatment was 60 (40-93) and all were female. Ninety percent of patients had invasive ductal carcinoma. The majority were poorly differentiated (60%). On PCR assay, none of the tumor samples tested positive for BLV DNA, despite having consistent signals in positive controls. CONCLUSION: We did not find BLV DNA in fresh-frozen breast cancer tumors from patients presenting to a hospital in Vermont. Our findings suggest a low prevalence of BLV in our patient population and a need to reevaluate the association between BLV and human breast cancer.

Breast cancer risk characteristics of women undergoing whole-breast ultrasound screening versus mammography alone.

BACKGROUND: There are no consensus guidelines for supplemental breast cancer screening with whole-breast ultrasound. However, criteria for women at high risk of mammography screening failures (interval invasive cancer or advanced cancer) have been identified. Mammography screening failure risk was evaluated among women undergoing supplemental ultrasound screening in clinical practice compared with women undergoing mammography alone. METHODS: A total of 38,166 screening ultrasounds and 825,360 screening mammograms without supplemental screening were identified during 2014-2020 within three Breast Cancer Surveillance Consortium (BCSC) registries. Risk of interval invasive cancer and advanced cancer were determined using BCSC prediction models. High interval invasive breast cancer risk was defined as heterogeneously dense breasts and BCSC 5-year breast cancer risk ≥2.5% or extremely dense breasts and BCSC 5-year breast cancer risk ≥1.67%. Intermediate/high advanced cancer risk was defined as BCSC 6-year advanced breast cancer risk ≥0.38%. RESULTS: A total of 95.3% of 38,166 ultrasounds were among women with heterogeneously or extremely dense breasts, compared with 41.8% of 825,360 screening mammograms without supplemental screening (p < .0001). Among women with dense breasts, high interval invasive breast cancer risk was prevalent in 23.7% of screening ultrasounds compared with 18.5% of screening mammograms without supplemental imaging (adjusted odds ratio, 1.35; 95% CI, 1.30-1.39); intermediate/high advanced cancer risk was prevalent in 32.0% of screening ultrasounds versus 30.5% of screening mammograms without supplemental screening (adjusted odds ratio, 0.91; 95% CI, 0.89-0.94). CONCLUSIONS: Ultrasound screening was highly targeted to women with dense breasts, but only a modest proportion were at high mammography screening failure risk. A clinically significant proportion of women undergoing mammography screening alone were at high mammography screening failure risk.

Indoleamine 2,3-Dioxygenase as a Therapeutic Target for Alzheimer's Disease and Geriatric Depression.

Neuroimmune-triggered neuroinflammation of the central nervous system is emerging as an important aetiopathogenic factor for multiple neurological disorders, including depression, dementia, Alzheimer's disease, multiple sclerosis and others. Tryptophan metabolism via the kynurenic pathway, which is initiated by the indoleamine-2,3-dioxygenase (IDO-1) enzyme, is a key regulator of the neuroimmune system and its associated neuroinflammatory effects. As discussed in this review, targeting the production of immunopathic and potentially neurotoxic kynurenine metabolites by inhibitory downregulation of IDO-1 may prove a viable target against inflammation-induced neurological conditions, particularly depression and dementia.

Outcomes of umbilical hernia repair in cirrhotic veterans: a VASQIP study.

PURPOSE: Umbilical hernia repair (UHR) in cirrhotics with ascites is a challenging problem associated with increased morbidity and mortality. This study examines the outcomes of UHR in veterans, comparing those undergoing elective versus emergent repair. METHODS: VASQIP was queried for all UHRs during the period 2008-2015. Data collection included demographics, operative details, Model for End-stage Liver Disease (MELD) score, and postoperative outcomes. Univariate and multivariate regression analyses were performed, and a p value of ≤ 0.05 was considered significant. RESULTS: A total of 383 patients were included in the analysis. Overall, mean age was 58.9, 99.0% were males, mean body mass index (BMI) was 26.7 kg/m2, 98.2% had American Society of Anesthesiologists (ASA) classification ≥ III, and 87.7% had independent functional status. More than 1/3 the patients underwent emergent UHR (37.6%). Compared with the elective UHR group, who underwent emergent repair were older, more likely to be functionally dependent, higher MELD score. Hypoalbuminemia, emergency repair and MELD score were found to be independent predictors of poor outcomes. CONCLUSION: UHR in cirrhotic veterans has worse outcomes when performed emergently. Diagnosis should be followed by medical optimization and elective repair, rather than waiting for an emergent indication in > 1/3 of patients.

The Immunopathy of Alzheimer's Disease: Innate or Adaptive?

Beyond the time-honoured targeting of protein misfolding and aggregation, Alzheimer's disease needs new, innovative therapeutic directions. When exploring alternative druggable mechanisms, multifaceted in vitro and in vivo data demonstrate that immune system dysfunction is a pivotal driver of Alzheimer's disease progression. In pursuing neuroimmunological targets, a major but often under-discussed consideration regards the issue of whether innate or adaptive immunity (or both) within the neuroimmune network should be the centre of focus when devising immunotherapeutic approaches to Alzheimer's. This perspective article briefly reviews current data, concluding that while both innate and adaptive immunity contributes to the immunopathology of Alzheimer's, the proinflammatory microglia and cytokines of innate immunity will provide higher yield targets with a greater likelihood of efficacy. Although it seems paradoxical to focus on a rapid, short-lived aspect of immunity when seeking approaches to a quintessentially chronic brain disease, accumulating evidence affords ample data to support the target-rich cascade of innate immunity for the development of much-needed new diagnostics and therapeutics.

Amyloid-ß is a cytokine.

The role of amyloid-ß (Aß) peptide in human physiology and pathology remains an unresolved subject of study; Aß's role in Alzheimer's disease (AD) is particularly controversial. However, before we can more fully appreciate Aß's role in AD, an understanding of its normal physiological role(s) must first be attained. This perspective appraises the current literature and concludes that Aß is a cytokine. This conclusion was arrived at based on a comprehensive listing of 30 characteristic defining structural and functional properties of cytokines followed by a literature precedence-based demonstration that Aß possesses all 30 properties; this categorization of cytokine characteristics enabled an organized comparison of cytokines and Aß, thereby providing systematic justification for classifying Aß as a cytokine. The conclusion that Aß is a cytokine enables the merger of two leading hypotheses of AD (amyloid hypothesis and neuroinflammation) into a single process.