Search

PURPOSE Cancer patients are at a higher risk of venous thromboembolism (VTE) than the general population. In the general population, blacks are at a higher risk of VTE compared with whites. The influence of race on cancer-associated VTE remains unexplored. We examined whether black cancer patients are at a higher risk of VTE and whether these differences are present in specific cancer types. DESIGN A retrospective study was performed in the largest safety net hospital of New England using a cohort of cancer patients characterized by a substantial number of nonwhites. RESULTS We identified 16,498 subjects with solid organ and hematologic malignancies from 2004 to 2018. Among them, we found 186 unique incident VTE events, of which the majority of the events accrued within the first 2 years of cancer diagnosis. Overall, blacks showed a 3-fold higher incidence of VTE (1.8%) compared with whites (0.6%; P

We completed a pilot study to guide the development of the VA Research Precision Oncology Data Commons infrastructure as a collaboration platform with the greater research community. Our results using a small subset of patients from the VA's Precision Oncology Program demonstrate the feasibility of our data sharing platform to build predictive models for lung cancer survival using machine learning, as well as highlight the potential of target genome sequencing data.

Background: Several studies have shown that cancer is associated with a 2 to 9-fold increased risk of venous thromboembolism (VTE) (Heit 2000; Hutton 2000; Hansson 2000; Prandoni 2002; Descourt 2006), with an absolute risk ranging from 1%-8% (Timp 2013). Importantly, the presence of VTE significantly reduces the 1-year survival rate from 36% in cancer patients without VTE to 12% in cancer patients with VTE (Sorensen 2000). Large cohort studies in the general population have suggested that Blacks compared to Whites are at higher risk of developing VTE (Zakai 2014). However, studies examining the influence of race on specific cancer-associated VTE have been scarce. To address racial disparities in cancer-associated VTE, we conducted a retrospective study in the largest safety-net hospital in New England, Boston Medical Center, with a large cancer cohort consisting of a substantial number of Black patients. This has provided a unique opportunity to directly compare the risk of specific cancer-associated VTE between Black and White cancer patients which could lead to future mechanisms-based studies. Methods: Summary statistics were performed and presented as mean, proportion and their respective standard deviation. Differences between blacks and whites for various variables were tested using Student's t-test, Pearson's Chi-square, and Fisher's exact test as appropriate using RStudio software (v1.0.153). Logistic regression was then used to estimate and compare odds of VTE occurrence in Lung cancer after adjusting for other confounders. Statistical significance was assessed at p Results: We analyzed 16,498 cases with all types of solid organ and hematologic malignancies from 2004 to present (2018) with case mix characterized by Whites (53%) and Blacks (33%) and Others (11.7%). Our review of the electronic medical record revealed that 238 (1.4%) of 16,498 cancer patients had VTE, either at presentation or within one year following the cancer diagnosis. Since some VTE cases might have been undiagnosed prior to cancer development/manifestation, we used the term cancer-associated VTE to denote co-existence of these pathologies. The proportion of VTE cases were similar among male (55.5%) and female patients (44.1%). Of 238 cases of cancer presenting with VTE, Blacks predominated with 121 cases (51.3%) compared to 65 cases of Whites (27.5%). Interestingly, selected cancers were more associated with VTE in Blacks. As shown in Table 1, a significantly higher proportion of cancer-associated VTE was observed in Black patients with lung cancer, >breast cancer, >prostate cancer, >colorectal cancer and gastric/small bowel cancer; in descending order. VTE occurrence was observed predominantly in the pulmonary artery (36.9%) and femoral/iliac vein (16.1%). Sixteen percent of patients with cancer-associated VTE experienced recurrent VTE, however, no statistical difference in race was seen (p= 0.6). Given the high number of cases of lung cancer with VTE, we examined the influence of race with adjustment for confounders. Our logistic regression model showed that Black lung cancer patients have a significantly higher odds of developing cancer-associated VTE even after adjusting for cancer stage, age, and sex (OR- 2.39, CI = 1.26-4.60, p = 0.0079). Interestingly, the proportions of VTE in cancers such as pancreatic cancer, head and neck cancer and glioblastoma, were equally observed in Black and White patients, which can be ascribed to low event rates of VTE in these cancers in this series. Conclusions: This single-center study suggests that a higher proportion of Black cancer patients exhibited cancer-associated VTE compared to White cancer patients. Importantly, this significant difference was especially reflected in specific cancer subtypes. Race had an independent effect on cancer-associated VTE but showed no significant influence on recurrent VTE. Our current investigation motivates additional large-scale studies of cohorts with substantial representation of Blacks and ethnic minorities to further identify factors that contribute to racial disparities in the context of cancer-associated VTE, thus guiding necessary interventions to maximize outcome. Our study also lays the ground for mechanistic cause-and-effect inquiries related to intricate associations of specific cancers with VTE in a certain races. Disclosures Brophy: Novartis: Research Funding.

The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G 1 phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna -/- cells resemble Rb -/- cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation.

Guanylin and uroguanylin induce natriuresis in mice lacking guanylyl cyclase-C receptor. Background Guanylin (GN) and uroguanylin (UGN) are intestinally derived peptide hormones that are similar in structure and activity to the diarrhea-causing Escherichia coli heat-stable enterotoxins (STa). These secretagogues have been shown to affect fluid, Na + , K + , and Cl − transport in both the intestine and kidney, presumably by intracellular cyclic guanosine monophosphate (cGMP)-dependent signal transduction. However, the in vivo consequences of GN, UGN, and STa on renal function and their mechanism of action have yet to be rigorously tested. Methods We hypothesized that intravenous administration of GN, UGN, or STa would cause an increase in natriuresis in wild-type mice via cGMP and guanylyl cyclase-C (GC-C, Gucy2c ), the only known receptor for these peptide-hormones, and that the peptide-induced natriuresis would be blunted in genetically altered mice devoid of GC-C receptors (GC-C (−/−) null). Results In wild-type mice using a modified renal clearance model, GN, UGN, and STa elicited significant natriuresis, kaliuresis, and diuresis as well as increased urinary cGMP levels in a time- and dose-dependent fashion. Absolute and fractional urinary sodium excretion levels were greatest ∼40 minutes following a bolus infusion with pharmacologic doses of these peptides. Unexpectedly, GC-C (−/−) null mice also responded to the GN peptides similarly to that observed in wild-type mice. Glomerular filtration rate (GFR), blood pressure, and plasma cGMP in the mice (wild-type or GC-C (−/−) null) did not significantly vary between the vehicle- and peptide-treatment groups. The effects of UGN may also influence long-term renal function due to down-regulation of the Na + /K + ATPase γ-subunit and the Cl − channel ClC-K2 by 60% and 75%, respectively, as assessed by differential display polymerase chain reaction (PCR) (DD-PCR) and Northern blot analysis of kidney mRNA from mice treated with UGN. Conclusion GN, UGN, and STa act on the mouse kidney, in part, through a cGMP-dependent, GC-C–independent mechanism, causing significant natriuresis by renal tubular processes. UGN may have further long-term effects on the kidney by altering the expression of such transport-associated proteins as Na + /K + ATPase and ClC-K2.

In primary mammalian cells, DNA replication initiates in a small number of perinucleolar, lamin A/C-associated foci. During S-phase progression in proliferating cells, replication foci distribute to hundreds of sites throughout the nucleus. In contrast, we find that the limited perinucleolar replication sites persist throughout S phase as cells prepare to exit the cell cycle in response to contact inhibition, serum starvation, or replicative senescence. Proteins known to be involved in DNA synthesis, such as PCNA and DNA polymerase delta, are concentrated in perinucleolar foci throughout S phase under these conditions. Moreover, chromosomal loci are redirected toward the nucleolus and overlap with the perinucleolar replication foci in cells poised to undergo cell cycle exit. These same loci remain in the periphery of the nucleus during replication under highly proliferative conditions. These results suggest that mammalian cells undergo a large-scale reorganization of chromatin during the rounds of DNA replication that precede cell cycle exit.

The brain of Alzheimer's disease (AD) patients contains deposits of amyloid beta-peptide (A beta). Recent studies have shown that A beta is a substrate for tissue transglutaminase (TGase), which induces the formation of cross-linked dimers and polymers, and that tacrine, indomethacin and deferoxamine, which have widely different chemical structures, attenuate the progression of symptoms of AD. This report evaluated the potential of a total of ten different pharmacological agents to inhibit TGase-induced cross-linking of A beta, including known TGase inhibitors (dansylcadaverine, spermine), non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid, diflunisal, salicylic acid), monoamine oxidase inhibitors (tranylcypromine, phenelzine), an acetylcholinesterase inhibitor (tacrine), and an iron chelating agent (deferoxamine). All but one (salicylic acid) of these ten agents had an inhibitory effect on TGase-induced A beta cross-linking. These results suggest that inhibition of TGase-induced cross-linking of A beta is a potential pharmacologic target for the treatment of AD. A method is also presented for the determination of percent inhibition of TGase-induced A beta cross-linking based on the separated monomer, dimer and polymer bands on SDS-PAGE gels.