Spleen tyrosine kinase (SYK) blocks autophagic Tau degradation in vitro and in vivo.

Spleen tyrosine kinase (SYK) plays a major role in inflammation and in adaptive immune responses and could therefore contribute to the neuroinflammation observed in various neurodegenerative diseases. Indeed, previously we have reported that SYK also regulates ß-amyloid (Aß) production and hyperphosphorylation of Tau protein involved in these diseases. Moreover, SYK hyperactivation occurs in a subset of activated microglia, in dystrophic neurites surrounding Aß deposits, and in neurons affected by Tau pathology both in individuals with Alzheimer's disease (AD) and in AD mouse models. SYK activation increases Tau phosphorylation and accumulation, suggesting that SYK could be an attractive target for treating AD. However, the mechanism by which SYK affects Tau pathology is not clear. In this study, using cell biology and biochemical approaches, along with immunoprecipitation and immunoblotting, quantitative RT-PCR, and ELISAs, we found that SYK inhibition increases autophagic Tau degradation without impacting Tau production. Using neuron-like SH-SY5Y cells, we demonstrate that SYK acts upstream of the mammalian target of rapamycin (mTOR) pathway and that pharmacological inhibition or knockdown of SYK decreases mTOR pathway activation and increases autophagic Tau degradation. Interestingly, chronic SYK inhibition in a tauopathy mouse model profoundly reduced Tau accumulation, neuroinflammation, neuronal and synaptic loss, and also reversed defective autophagy. Our results further suggest that the SYK up-regulation observed in the brains of individuals with AD contributes to defective autophagic clearance leading to the accumulation of pathogenic Tau species. These findings further highlight SYK as a therapeutic target for the treatment of tauopathies and other neurodegenerative proteinopathies associated with defective autophagic clearance.

Cancer, diabetes, survival and glycemic control: a large multisite analysis.

Aim: To determine overall survival (OS) and glycemic control in patients with cancer and diabetes. Materials & methods: Patients of our institution with breast, colon, lung, pancreas and prostate cancer were retrospectively reviewed. OS was compared between matched patients with and without diabetes, and changes in glucose value over time were assessed. Results: For 3934 patients each with and without diabetes, adjusted analysis showed no difference in OS according to diabetes status (hazard ratio: 1.07; 95% CI: 0.96-1.20). Mean glucose values decreased over time in patients with and without diabetes (p = 0.01). Conclusion: In this large study of patients with five common cancers, the co-occurrence of diabetes did not affect OS. Cancer did not adversely affect glucose levels.

The aim of this study was to evaluate survival and glucose control in patients with cancer and diabetes at three separate geographic locations in a single health system. From an institutional cancer registry, we identified patients with breast, colon, lung, pancreas and prostate cancers. Patients with and without diabetes were matched by age, sex, cancer type, staging, geographic location and year of cancer diagnosis. In this study, the co-occurrence of diabetes did not affect overall survival. Cancer did not adversely affect glucose levels.

Survival and glycemic control in patients with co-existing squamous cell carcinoma and diabetes mellitus.

AIM: This study examined the impact of diabetes mellitus (DM) on survival in squamous cell carcinoma (SCC) patients, and the impact of SCC on glycemic control. MATERIALS & METHODS: Patients with newly diagnosed SCC with and without DM were matched 1:1 (2007-2017). Overall survival and recurrence-free survival were estimated using the Kaplan-Meier method. Hemoglobin A1c (HbA1c) and glucose level during the year following cancer diagnosis were compared using mixed models. RESULTS: HbA1c decreased over time in DM patients (p = 0.04). The 5-year overall survival was 61% in DM patients, compared with 78% in patients without DM (p = 0.004). CONCLUSION: The presence of co-existing DM adversely impacted survival in patients with SCC. SCC did not affect glycemic control.

Implications of neuroendocrine tumor and diabetes mellitus on patient outcomes and care: a matched case-control study.

AIM: We aimed to determine the impact of diabetes mellitus (DM) on survival of patients with neuroendocrine tumors (NETs) and of NETs on glycemic control. PATIENTS & METHODS: Patients with newly diagnosed NETs with/without DM were matched 1:1 by age, sex and diagnosis year (2005-2017), and survival compared (Kaplan-Meier and Cox proportional hazards). Mixed models compared hemoglobin A1c (HbA1c) and glucose during the year after cancer diagnosis. RESULTS: Three-year overall survival was 72% (95% CI: 60-86%) for DM patients versus 80% (95% CI: 70-92%) for non-DM patients (p = 0.82). Hazard ratio was 1.33 (95% CI: 0.56-3.16; p = 0.51); mean DM HbA1c, 7.3%. CONCLUSION: DM did not adversely affect survival of patients with NET. NET and its treatment did not affect glycemic control.

Prognosis and outcome of small (<=1 cm), node-negative breast cancer on the basis of hormonal and HER-2 status.

Long-term outcomes and hence the role of adjuvant therapy in patients with small (≤1 cm), node-negative breast cancer remain unclear. This study's objective was to evaluate whether human epidermal growth factor receptor (HER)-2 status is an independent, poor prognostic marker in patients with these tumors and to identify a subgroup of patients with these small tumors who might benefit from adjuvant systemic therapy. All patients with a diagnosis of a node-negative breast tumor measuring ≤1 cm and available HER-2 test results between January 1, 2001, and December 31, 2005, at the three Mayo Clinic sites were identified. Clinicopathologic data were compared in three groups: HER-2(-), HER-2(+), and triple-negative (TN) tumors. Of the 421 tumors identified, 364 (86.5%) were HER-2(-), 28 (6.7%) were HER-2(+), and 29 (6.9%) were TN. The median follow-up time was 1,015 days (range, 1-2,549 days). Groups were balanced in terms of patient age and tumor histology. Eleven patients with HER-2(-) tumors (3.0%), seven with HER-2(+) tumors (25.0%), and eight with TN tumors (27.6%) received adjuvant chemotherapy. Follow-up data were available for 357, 28, and 28 patients in the three groups, respectively. Death rates in the three groups were 6.4% (23 of 357) (one recurrence-related death), 0% (0 of 28), and 7.1% (2 of 28) (one recurrence-related death), respectively. During follow-up, the tumor recurred in nine patients: four were HER-2(-) tumors (1.1%), two were HER-2(+) tumors (7.1%), and three were TN tumors (10.7%). Patients with small, node-negative breast tumors have an excellent prognosis, but HER-2(+) and TN tumors appear to have a higher recurrence rate, warranting consideration for broad use and optimization of systemic adjuvant treatments.

Assessing the relationship between institutional cancer and diabetes mortality rates using National Death Index data.

AIM: To evaluate overall survival (OS), glycemic control in cancer patients with and without diabetes mellitus (DM). PATIENTS & METHODS: Patients (2010-2015) with newly diagnosed prostate, breast, lung, colorectal and pancreatic cancers were identified in institutional cancer registry. Data linked to National Death Index for vital status. 5-year OS estimated; glucose and hemoglobin A1c assessed during year postdiagnosis. RESULTS: We identified 1404 patients (non-DM, n = 936; DM, n = 468). DM cohort had 168 deaths (36%); non-DM, 267 (29%). 5-year OS estimated at 58% (95% CI: 53-64%) for DM and 67% (95% CI: 64-71%) for controls; for matched pairs, hazard ratio: 1.35 (95% CI: 1.02-1.79). Cancer did not harm glycemic control. CONCLUSION: OS among cancer patients with DM was lower than without DM.

Mortality and glycemic control among patients with diabetes mellitus and uterine or ovarian cancer.

AIM: To evaluate associations between survival and glycemic control in age-matched patients with endometrial or ovarian cancer, with/without diabetes mellitus (DM). PATIENTS & METHODS: Patients with newly diagnosed ovarian or endometrial cancer with and without DM were compared. RESULTS: The study included 84 patients with ovarian cancer (28, DM); 96 with endometrial cancer (48 with, 48 without DM). DM patients did not have worse overall or progression-free survival than non-DM patients. Glycemic control was not associated with either cancer. CONCLUSION: There was no association between DM and survival for patients with uterine or ovarian cancer. In addition, there was no association between uterine and ovarian cancer and glycemic control. Additional studies to confirm these observations in larger populations are required.

Mortality and glycemic control among patients with acute and chronic myeloid leukemia and diabetes: a case-control study.

AIM: We examined the association between diabetes and survival in patients with acute and chronic myeloid leukemia and the association of leukemia with glycemic control. PATIENTS & METHODS: Patients with leukemia with and without diabetes (2007-2015) were retrospectively identified and matched 1:1 (n = 70 per group). Overall survival was estimated by the Kaplan-Meier method. Hemoglobin A1c and glucose levels the year after leukemia diagnosis were compared by mixed models. RESULTS: Among 25 of 70 patients with diabetes, mean hemoglobin A1c during the year after leukemia diagnosis was 6.8%. Kaplan-Meier-estimated 3-year survival was 46% for diabetes patients versus 45% for controls (p = 0.79). CONCLUSION: No associations were found between leukemia, diabetes, survival and glycemic control.

Survival and glycemic control in patients with coexisting lymphoma and diabetes: a case-control analysis.

AIM: We examined the effect of diabetes on survival in patients with lymphoma and the effect of lymphoma on glycemic control. PATIENTS & METHODS: Patients with lymphoma with and without diabetes (2005-2016) were retrospectively identified and matched 1:1. Overall survival and progression-free survival were estimated by the Kaplan-Meier method. Hemoglobin A1c (HbA1c) and glucose levels during the year after cancer diagnosis were compared by mixed models. RESULTS: For patients with diabetes, mean HbA1c during the year after lymphoma diagnosis was 6.7%. Estimated 5-year progression-free survival for patients with versus without diabetes was 63% (95% CI: 53-76%) versus 58% (95% CI: 46-71%) (p = 0.42). CONCLUSION: Lymphoma and its treatment did not affect glycemic control. Diabetes did not decrease lymphoma-specific survival.

Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities.

Several genetic variants of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) have been shown to increase the risk of developing Alzheimer's disease (AD) supporting a role of microglia and immune cells in the pathobiology of AD. We have employed an ectopic model of TREM2 and DAP12 expression in HEK293 cells to study selectively TREM2 dependent signaling and phagocytic functions and evaluated the effects of some of the TREM2 mutations associated with AD. We show that shedding of the TREM2 N-terminal domain does not affect the inhibition of NFκB activation induced by TREM2 while it completely blocks phagocytosis suggesting that TREM2 anti-inflammatory properties can be mediated by the TREM2 C-terminal fragment while the phagocytic activity requires the full-length receptor. In addition, we confirm in that model that apolipoprotein E (APOE) is a ligand for TREM2 and triggers TREM2 signaling. In particular, we show that APOE4 stimulates spleen tyrosine kinase (SYK) activation more potently than APOE2 in a TREM2 dependent manner. Interestingly, TREM2 appears to antagonize NFκB activation induced by phorbol ester but is unable to prevent TNFα induction of NFκB activation suggesting that TREM2 antagonizes inflammatory events triggered downstream of PKC. TREM2 mutations drastically impact TREM2 phagocytosis as well as its ability to antagonize NFκB activation and notably prevent the activation of the PI3K/AKT pathway observed with wild-type TREM2. Overall our data suggest that TREM2 dependent phagocytosis requires an activation of the SYK/PI3K/AKT/PLCγ pathways while the suppression of NFκB activation by TREM2 is independent of SYK, PI3K, and PLCγ activities. This model of ectopic TREM2-DAP12 co-expression appears suitable to study TREM2 signaling as several biological functions of TREM2 and TREM2 mutations that have been previously described in myeloid and microglial cells were also replicated in this model.

Leptomeningeal Carcinomatosis in Colorectal Cancer: The Mayo Clinic Experience.

BACKGROUND: Leptomeningeal metastasis (LM) is an uncommon form of metastatic disease in many cancers. There remains a paucity of literature with regard to the course and management of LM in colorectal cancers (CRCs). The aim of this study was to estimate the incidence of LM in patients with CRC seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. METHODS: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. RESULTS: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. Median overall survival after CRC diagnosis was 25.7 months (range, 4.7-74.8 months). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range, 0-68.1 months). All patients had magnetic resonance imaging findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, and 1 with both. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in 2 cases. Seven patients (78%) had palliative radiotherapy for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. Median survival after LM diagnosis was 7 weeks (range, 2-39 weeks). CONCLUSIONS: LM is an exceedingly rare development in the natural course of CRC. It confers a poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving radiotherapy to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.