Citations

Context.— Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. Objective.— To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. Data Sources.— English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. Conclusions.— This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Abstract Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by young serum in a transgenic AD mouse model. We found that young serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Neutrophil depletion via Ly6G neutralizing antibodies mimicked the benefits of young serum on AD brain functions. Serum proteomic analysis of young serum revealed significant enrichment of the factors VEGF-A and CXCL1, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Intravenously injected VEGF-A reversed Aβ-induced decreases in Cdk5 and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration and thereby restored memory in APP/PS1 mice. Our data uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and provide a rationale for targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.

Abstract Background and purpose: Poor ST-segment resolution (STR) is strongly associated with poor prognosis in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). previous studies suggested higher HCY level in the people who live in high altitudes, so a retrospective analysis is conducted to examine the potential relationship between elevated serum HCY and poor STR after PPCI at high altitudes. Methods: This retrospective analysis included 308 high-altitude dwelling patients (1800-2200 meters elevation from the sea level) undergoing PPCI for STEMI during a period from September 2021 to March 2022. Clinical data were collected and statistically analyzed. Results: In comparison to the patients with normal plasma homocysteine (≤15 mmol/L; n = 155), patients with elevated homocysteine (>15 mmol/L) had higher percentage of men (92.81% vs. 80.00%; p = 0.001) and smoker (79.08% vs. 63.87%; p = 0.003), but no difference in other key baseline characteristics. The rate of complete ST-segment resolution after PPCI (≥ 70%) was 83.23% in the control group and 49.67% in the elevated HCY group (p ≤ 0.001). In multivariable regression analysis, poor ST-segment resolution (<70%) was independently associated with longer pain-to-balloon time (OR 0.832; 95%CI: 0.775–0.894), lower uric acid (OR 1.003; 95%CI: 1.000-1.005), and elevated HCY (OR 0.957 vs. normal HCY; 95%CI: 0.937–0.977). Conclusion: Elevated plasma HCY level was associated with poor ST segment resolution in patients undergoing PPCI STEMI at high altitude.

AbstractPeripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA ( P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA ( P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis ( P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

Abstract While epoxyeicosatrienoic acids (EETs) have been implicated in breast cancer growth and progression, less is known about their effects on oncogene transcription. We have previously found that the oncogenic regioisomer (±)14,15-EET drives mitochondrial respiration, ATP synthesis, and proliferation of ER+/HER2- breast cancer cells [Cell Chem Biol. 2017 Oct 19;24(10):1259-1275]. RNAseq analysis was performed (5 replicates per condition) on serum starved (16 hours) MCF-7 cells which were then treated with (±)14,15-EET or vehicle (2 hours; serum and phenol red free medium without estradiol). Using gene set enrichment analysis (GSEA), we found that (±)14,15-EET activated an estrogen receptor alpha (ER) hallmark early response gene set and synchronously activated a MYC hallmark gene set. With activation of the MYC hallmark gene set, c-Myc gene expression was also induced at 2 hours (3.99-fold; P=2.3 x 10-17; FDR=2.8 x 10-14). These data suggest an alternative pathway for activation of estrogen and MYC regulated genes in the absence of estradiol. The 15 genes most transcriptionally activated by (±)14,15-EET at 2 hours were: VMP1, ZFP36, JUNB, FOS, IER3, EGR1, IER5L, ELF3, JUN, NR4A1, HES1, DUSP1, MYC, TOB1, and CITED2 [fold change range: 3.25 (CITED2) to 90.5 (FOS); all P&lt; 2.86 x 10-17; all FDR &lt; 3.03 x 10-14]. The ER regulated genes most transcriptionally activated (&gt;1.5 fold) were: IER3, TOB1, AREG, CISH, KCNMB3, and PDK4 (fold change range: 1.77 to 4.35; P= 1.74 x 10-18 to 1.35 x 10-5; FDR=5.54 x 10-15 to 6.4 x 10-4). The MYC regulated genes most transcriptionally activated (&gt; 1.5-fold change) were EIF4A1 (fold change= 2.37; P=1.0 x 10-7; FDR=1.33 x 10-5), IRF9 (fold change=1.58; P=0.0044; FDR= 0.026), and FOSL1 (fold change=1.51; P=0.008; FDR=0.04). Supporting the hypothesis of (±)14,15-EET activation of ER-regulated transcription, (±)14,15-EET promoted nuclear translocation of ER at 1 hour measured by DAPI normalized immunofluorescence [MCF-7 nuclear ER increase of 1.66-fold (P=0.031); ZR75-1 nuclear ER increase of 1.77-fold (P=0.015)]. Supporting the hypothesis of (±)14,15-EET activation of MYC-regulated transcription, (±)14,15-EET treatment promoted nuclear translocation of c-Myc with MCF-7 cells exhibiting a 1.22-fold increase at 2 hours (P=0.002). (±)14,15-EET also promoted nuclear translocation of FITC-70 kDa dextran with MCF-7 cells exhibiting an increase of 1.35-fold at 1 hour (P=0.029). These data suggest that (±)14,15-EET can induce an estradiol-like immediate early gene response in ER+/HER2- breast cancer cells correlating with c-Myc activation. In summary, while the effect of (±)14,15-EET on nuclear translocation may be partially cargo agnostic, (±)14,15-EET promotes ER and c-Myc nuclear translocation and associated transcription, mimicking a tandem hormonal and growth factor response. Citation Format: Jianxun Lei, Zhijun Guo, Julissa Molina-Vega, Paloma Cervantes, Swaathi Jayaraman, John R. Hawse, Carlos Perez, Juan Abrahante, Xiaojia Tang, Krishna Kalari, Jinhua Wang, John R. Falck, Carol Lange, Matthew P. Goetz, David Potter. (±) 14,15-epoxyeicosatrienoic acid induces hallmark ER and MYC gene expression and associated ER and c-Myc nuclear translocation in ER+/HER2- breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB564.

Precision oncology is expected to improve selection of targeted therapies, tailored to individual patients and ultimately improve cancer patients’ outcomes. Several cancer genetics knowledge databases have been successfully developed for such purposes, including CIViC and OncoKB, with active community-based curations and scoring of genetic-treatment evidences. Although many studies were conducted based on each knowledge base respectively, the integrative analysis across both knowledge bases remains largely unexplored. Thus, there exists an urgent need for a heterogeneous precision oncology knowledge resource with computational power to support drug repurposing discovery in a timely manner, especially for life-threatening cancer. In this pilot study, we built a heterogeneous precision oncology knowledge resource (POKR) by integrating CIViC and OncoKB, in order to incorporate unique information contained in each knowledge base and make associations amongst biomedical entities (e.g., gene, drug, disease) computable and measurable via training POKR graph embeddings. All the relevant codes, database dump files, and pre-trained POKR embeddings can be accessed through the following URL: https://github.com/shenfc/POKR.