scholarly journals A RAC-GEF network critical for early intestinal tumourigenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
K. A. Pickering ◽  
K. Gilroy ◽  
J. W. Cassidy ◽  
S. K. Fey ◽  
A. K. Najumudeen ◽  
...  

AbstractRAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2−/−Vav3−/−Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 977-977
Author(s):  
Elysia Alvarez ◽  
Helen Parsons ◽  
Frances Maguire ◽  
Yi Chen ◽  
Cyllene Morris ◽  
...  

Abstract Introduction: Adolescent and young adult (AYAs: 15-39) patients with cancer have not had the same relative improvement in survival as other age groups over the last decades. Studies have shown that having public insurance or being uninsured at diagnosis is associated with more advanced disease at presentation and worse overall survival. However, previous studies have not differentiated patients who joined Medicaid at diagnosis from those with continuous enrollment which may have different implications for access to care prior to diagnosis. Therefore, we examined the impact of insurance status, including Medicaid enrollment at diagnosis, on stage at diagnosis for AYAs with non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) only] and on survival for AYAs with NHL, HL, acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL). Methods: Using Medicaid enrollment data linked to the California Cancer Registry, we identified AYAs with NHL, HL, ALL, and AML diagnosed from 2005 to 2014. Insurance type was classified as: continuous Medicaid, discontinuous Medicaid prior to diagnosis, Medicaid at diagnosis, other public (Medicare, Indian/Public Health Service, county), private/military, and uninsured. Multivariable logistic regression and Cox proportional hazards regression were used to determine the impact of insurance type on stage at diagnosis (for NHL and HL) and overall survival, respectively. Results are represented as adjusted odds ratios (OR) and hazard ratios (HR) with associated 95% confidence intervals (CI). Results: Of the 11,667 AYA patients in our study, 4,435 had NHL, 4,161 had HL, 1,522 had AML and 1,549 had ALL. Patients with HL had the highest proportion of private insurance (66%) followed by those with NHL (60%), AML (50%) and ALL (37%). Of the 4,059 patients enrolled in Medicaid, 41% had continuous Medicaid, 15% had discontinuous Medicaid and 43% received Medicaid at diagnosis. Only 2-4% of patients, depending on primary diagnosis, remained uninsured after cancer diagnosis. The majority of AYAs with HL and NHL were diagnosed with stage I/II disease (59% and 52% respectively). Compared to AYAs with private insurance, NHL and HL patients with discontinuous Medicaid and Medicaid at diagnosis had a higher likelihood of later stage disease (III-IV vs I/II) at diagnosis (NHL: discontinuous OR 1.45, CI 1.10-1.92; at diagnosis OR 1.69, CI 1.38-2.06; HL: discontinuous OR 1.63, CI 1.19-2.23; at diagnosis OR 1.68, CI 1.35-2.09) after adjusting for sociodemographic factors, baseline comorbidities and type of facility. In addition, NHL patients with continuous Medicaid (OR 1.23, CI 1.01, 1.51) and HL patients with other public insurance (OR 1.56, CI 1.05-2.32) had a higher odds of late stage disease. Type of health insurance was associated with overall survival in multivariable models (Table). NHL patients with Medicaid (continuous HR 1.74, CI 1.39-2.17; discontinuous HR 2.52, CI 1.94-3.27; at diagnosis HR 1.88, CI 1.53-2.31), other public (HR 1.83, CI 1.16-2.87) and no insurance (HR 1.87, CI 1.09-3.20) had worse survival than NHL patients with private insurance. Similarly, HL patients with Medicaid (continuous HR 2.10, CI 1.42-3.12; discontinuous HR 1.89, CI 1.08-3.29; at diagnosis HR 2.43, CI 1.699-3.48) and no insurance (HR 1.87, CI 1.09-3.20) experienced worse survival. For AML, health insurance was not significantly associated with survival. For ALL, only continuous Medicaid (HR 1.32, CI 1.05-1.67) and other public (HR 1.32, CI 1.05-1.67) insurance were associated with worse survival, though discontinuous Medicaid trended toward significance (p=0.06). Conclusion: Our study demonstrates that a significant proportion of patients previously thought to have public insurance were discontinuously insured with Medicaid or uninsured at time of diagnosis, only receiving Medicaid after diagnosis. While important, insurance enrollment at diagnosis does not provide the same pre-diagnosis access to services as those with continuous enrollment. Indeed, for NHL and HL, we observed the strongest associations between discontinuous Medicaid and Medicaid at diagnosis and late stage disease. However, Medicaid, regardless of type of enrollment, was associated with worse survival in AYAs with NHL, HL and ALL relative to private insurance. Therefore, future studies should focus on factors influencing worse outcomes for AYA patients with public insurance. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 528-528
Author(s):  
Maxwell Roger Lloyd ◽  
Sarah Jo Stephens ◽  
Julian C. Hong ◽  
Ted A. James ◽  
Tejas Mehta ◽  
...  

528 Background: During the SARS-CoV-2 pandemic, routine screening mammography (SM) was stopped and diagnostic mammography (DM) was limited for several months across the United States in order to reduce patient exposure and redeploy medical personnel. We hypothesized that this delay would result in patients presenting with later-stage disease following the initial shutdown. Methods: Patients diagnosed with invasive breast cancers from 2016-2020 were identified using the Beth Israel Deaconess Medical Center Cancer Registry. Baseline patient characteristics, demographics, and clinical information were gathered and cross-referenced with our electronic medical record. Late-stage disease was defined as initial anatomic stage III-IV disease in the AJCC 8th edition staging system. The control cohort consisted of patients diagnosed from 2016-2019; patients diagnosed in 2020 were the test cohort. Chi-squared analysis was used to compare monthly distributions in stage at diagnosis between the control and test cohorts. Multivariate analysis was performed using a logistic regression model. Results: There were 1597 patients diagnosed with invasive breast cancer between 2016-2019 and 333 in 2020. Median age at diagnosis was 60 years; 99% were female, and 69.1% were white. Mammography was limited from 3/16/20-6/8/20, with 90% reduction in volume during this time. The number of screening studies performed in March, April, May, and June of 2020 were 987, 1, 4, and 721 compared to 2042, 2141, 2241, and 2142 in 2019. The volume of new diagnoses per month decreased substantially during the shutdown (see table). The proportion of patients diagnosed with late-stage disease was 6.6% in the control cohort compared to 12.6% in the 2020 test cohort (p < 0.001); 92.9% of late-stage diagnoses in 2020 occurred from June to December following the shutdown period. On multivariate analysis, year of diagnosis (2020 vs 2016-2019; OR = 4.25 95% CI 0.035-0.095, p < 0.001), lower income (<200% of the federal poverty level; OR = 2.73 95% CI 0.016-0.099, p = 0.006) and increased Charlson Comorbidity Index (OR = 12.01 95% CI 0.037-0.052, p < 0.001) were associated with later stage at diagnosis. Conclusions: Patients were more likely to be diagnosed with late-stage breast cancer following the global shutdown due to the SARS-CoV-2 pandemic. Patients with lower income and medical comorbidities were disproportionately affected. These data raise significant concerns regarding the impact of SARS-CoV-2 on cancer diagnoses and long-term outcomes, especially in vulnerable patient populations.[Table: see text]


AIDS ◽  
2012 ◽  
Vol 26 (18) ◽  
pp. 2275-2284 ◽  
Author(s):  
José M. Marcelino ◽  
Pedro Borrego ◽  
Charlotta Nilsson ◽  
Carlos Família ◽  
Helena Barroso ◽  
...  

Author(s):  
Marissa B. Lawson ◽  
Christoph I. Lee ◽  
Daniel S. Hippe ◽  
Shasank Chennupati ◽  
Catherine R. Fedorenko ◽  
...  

Background: The purpose of this study was to determine factors associated with receipt of screening mammography by insured women before breast cancer diagnosis, and subsequent outcomes. Patients and Methods: Using claims data from commercial and federal payers linked to a regional SEER registry, we identified women diagnosed with breast cancer from 2007 to 2017 and determined receipt of screening mammography within 1 year before diagnosis. We obtained patient and tumor characteristics from the SEER registry and assigned each woman a socioeconomic deprivation score based on residential address. Multivariable logistic regression models were used to evaluate associations of patient and tumor characteristics with late-stage disease and nonreceipt of mammography. We used multivariable Cox proportional hazards models to identify predictors of subsequent mortality. Results: Among 7,047 women, 69% (n=4,853) received screening mammography before breast cancer diagnosis. Compared with women who received mammography, those with no mammography had a higher proportion of late-stage disease (34% vs 10%) and higher 5-year mortality (18% vs 6%). In multivariable modeling, late-stage disease was most associated with nonreceipt of mammography (odds ratio [OR], 4.35; 95% CI, 3.80–4.98). The Cox model indicated that nonreceipt of mammography predicted increased risk of mortality (hazard ratio [HR], 2.00; 95% CI, 1.64–2.43), independent of late-stage disease at diagnosis (HR, 5.00; 95% CI, 4.10–6.10), Charlson comorbidity index score ≥1 (HR, 2.75; 95% CI, 2.26–3.34), and negative estrogen receptor/progesterone receptor status (HR, 2.09; 95% CI, 1.67–2.61). Nonreceipt of mammography was associated with younger age (40–49 vs 50–59 years; OR, 1.69; 95% CI, 1.45–1.96) and increased socioeconomic deprivation (OR, 1.05 per decile increase; 95% CI, 1.03–1.07). Conclusions: In a cohort of insured women diagnosed with breast cancer, nonreceipt of screening mammography was significantly associated with late-stage disease and mortality, suggesting that interventions to further increase uptake of screening mammography may improve breast cancer outcomes.


2002 ◽  
Vol 36 (6) ◽  
pp. 805-811 ◽  
Author(s):  
Sanjiv K. Jain ◽  
Philip W. Pemberton ◽  
Alexander Smith ◽  
Raymond F.T. McMahon ◽  
Peter C. Burrows ◽  
...  

2018 ◽  
Author(s):  
Joakim Esbjörnsson ◽  
Fredrik Månsson ◽  
Hans Norrgren ◽  
Sarah L. Rowland-Jones

In this study, we show that the pathogenic HIV-1 CXCR4-tropism is more common in HIV-1 single (79%) than in HIV-1 and HIV-2 dual-infected individuals (35%), suggesting that contemporaneous HIV-2 infection can affect HIV-1 co-receptor tropism in late-stage disease. Understanding the underlying mechanisms responsible for this natural alteration by HIV-2 could pave the way towards a deeper understanding of the AIDS pathogenesis.


2019 ◽  
Vol 220 (7) ◽  
pp. 1172-1177 ◽  
Author(s):  
Mark J Siedner ◽  
Mwebesa Bosco Bwana ◽  
Stephen Asiimwe ◽  
Gideon Amanyire ◽  
Nicholas Musinguzi ◽  
...  

Abstract Chronic inflammation predicts complications in persons with human immunodeficiency virus infection. We compared D-dimer, soluble CD14, and interleukin 6 levels before and 12 months after antiretroviral therapy (ART) initiation, among individuals starting ART during earlier-stage (CD4 T-cell count >350/µL) or late-stage disease (CD4 T-cell count <200/µL). Female sex, older age, viral load, and late-stage disease were associated with pre-ART biomarkers (n = 661; P < .05). However, there were no differences in biomarkers by disease stage after 12 months of ART (n = 438; P > .05), owing to loss from observation and greater declines in biomarkers in late-stage initiators (P < .001). Earlier initiation of ART is associated with decreased inflammation, but levels seem to converge between earlier and later initiators surviving to 12 months.


1995 ◽  
Vol 109 (4) ◽  
pp. 300-303 ◽  
Author(s):  
Bharath Singh

AbstractThe place of conservative treatment in sinogenic orbital complications has not been fully explained in the literature. The question that remains unresolved is – at which stage of the disease is surgery indicated?A study was undertaken in 240 patients with sinogenic orbital complications, to determine this. The patients were divided into three groups according to the stage of the disease as determined clinically: Group 1 (52 patients) with early stage disease, as detected by cellulitis only; Group 2 (76 patients) with intermediate stage, as detected by periorbital cellulitis and proptosis, but with full range of eye movement and unaltered vision: Group 3 (122 patients) with late stage disease, as detected by periorbital cellulitis and gross proptosis. with limitation of eye movement and altered vision.Group I and Group 2 patients were treated conservatively, with intravenous antibiotics and antral lavage. Group 3 patients were treated with intravenous antibiotics and surgery. External frontoethmoidectomy was performed in 31 (bilateral in two), ethmoidectomy in 91 (bilateral in five), sphenoidectomy in 15 and bilateral antral washout in all (122 patients). There was 100 per cent success with conservative treatment in Group 1 patients, whilst in Group 2 there was 98.6 per cent failure. The 75 patients in whom conservative treatment failed were successfully treated with surgery: frontoethmoidectomy was performed in 66 and ethmoidectomy in nine. In Group 3 patients, 100 per cent success was achieved with intravenous antibiotics and surgery.Sinogenic orbital complications can be treated conservatively and surgically, depending on the stage of the disease on presentation. Conservative treatment is only suitable for early complications, i.e. patients with periorbital cellulitis only. For disease beyond this stage i.e. intermediate and late stage disease, surgery is the treatment of choice.


Stem Cells ◽  
2016 ◽  
Vol 35 (2) ◽  
pp. 532-544 ◽  
Author(s):  
Annie C. Bowles ◽  
Amy L. Strong ◽  
Rachel M. Wise ◽  
Robert C. Thomas ◽  
Brittany Y. Gerstein ◽  
...  

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