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Data on the population‐based incidence of cancer‐associated venous thromboembolism (VTE) from racially diverse populations are limited. To evaluate the incidence and burden of cancer‐associated VTE, including demographic and racial subgroups in the general population of Oklahoma County—which closely mirrors the United States. A population‐based prospective study. We conducted surveillance of VTE at tertiary care facilities and outpatient clinics in Oklahoma County, Oklahoma, from 2012–2014. Surveillance included reviewing all imaging reports used to diagnose VTE and identifying VTE events from hospital discharge data and death certificates. Cancer status was determined by linkage to the Oklahoma Central Cancer Registry. We used Poisson regression to calculate crude and age‐adjusted incidence rates of cancer‐associated VTE per 100 000 general population per year, with 95% confidence intervals (95% CI). The age‐adjusted incidence (95% CI) of cancer‐associated VTE among adults age ≥ 18 was 70.0 (65.1–75.3). The age‐adjusted incidence rates (95% CI) were 85.9 (72.7–101.6) for non‐Hispanic Blacks, 79.5 (13.2–86.5) for non‐Hispanic Whites, 18.8 (8.9–39.4) for Native Americans, 15.6 (7.0–34.8) for Asian/Pacific Islanders, and 15.2 (9.2–25.1) for Hispanics. Recurrent VTE up to 2 years after the initial diagnosis occurred in 38 of 304 patients (12.5%) with active cancer and in 34 of 424 patients (8.0%) with a history of cancer > 6 months previously. Age‐adjusted incidence rates of cancer‐associated VTE vary substantially by race and ethnicity. The relatively high incidence rates of first VTE and of recurrence warrant further assessment of strategies to prevent VTE among cancer patients.

Data on the population‐based incidence of cancer‐associated venous thromboembolism (VTE) from racially diverse populations are limited.

Sickle cell disease (SCD) is associated with increased risk of poor health outcomes from respiratory infections, including COVID-19 illness. We used US death data to investigate changes in SCD-related mortality before and during the COVID-19 pandemic. We estimated annual age- and quarter-adjusted SCD-related mortality rates for 2014-2020. We estimated the number of excess deaths in 2020 compared with 2019 using the standardized mortality ratio (SMR). We found 1023 SCD-related deaths reported in the United States during 2020, of which 86 (8.4%) were associated with COVID-19. SCD-related deaths, both associated and not associated with COVID-19, occurred most frequently among adults aged 25-59 years. The SCD-related mortality rate changed <5% year to year from 2014 to 2019 but increased 12% in 2020; the sharpest increase was among adults aged ≥60 years. The SMR comparing 2020 with 2019 was 1.12 (95% CI, 1.06-1.19). Overall, 113 (95% CI, 54-166) excess SCD-related deaths occurred in 2020.

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P < .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P = .40) and VWD type (P = .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

Data on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P= .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P< .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P= .40) and VWD type (P= .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

•Machine learning natural language processing models can be an effective method for identifying venous thromboembolism in free-text reports•The highest performing models use vectorization rather than bag-of-words, and deep learning techniques, like convolutional neural networks

Background

Background:

Renal anomalies occur in about three infants per 1000 live births and have been associated with several environmental risk factors. Researchers have yet to assess the effect of maternal febrile illnesses on renal anomalies, even though febrile illnesses have been associated with other birth defects. Our objective was to determine whether maternal illness, fever, or medication use during the first trimester of pregnancy is associated with the occurrence of renal anomalies.In this population‐based case‐control study, we evaluated 192 infants with renal anomalies (renal agenesis [n = 44], obstructive defects [n = 134], and renal duplication defects [n = 14]) and 3029 infant without birth defects, all of whom were born in metropolitan Atlanta, Georgia, from 1968 through 1980. Maternal illness was defined as reported flu‐like illness and/or episodic illness during the first trimester.Our adjusted multivariate analyses showed that among the 192 case‐infants, 38 had mothers with an illness (adjusted odds ratio [AOR], 1.71; 95% confidence interval [CI], 1.15–2.52), 20 had mothers who reported a fever (AOR, 1.80; 95% CI, 1.07–3.02) and 26 had mothers who reported taking medication (AOR, 1.69; 95% CI, 1.07–2.68). Fifteen mothers reported a fever and medication use (AOR, 1.90; 95% CI, 1.05–3.45). Nonprescription aspirin‐containing medication use showed the strongest association (AOR, 3.45; 95% CI, 1.36–8.75) with renal anomalies.Our data suggest that maternal exposure to illness, fever, and medication (particularly aspirin) may increase the risk of congenital renal anomalies. Birth Defects Research (Part A), 2003. © 2003 Wiley‐Liss, Inc.

Vav family proteins are members of the Dbl family of guanine nucleotide exchange factors and activators of Rho family small GTPases. In addition to the Dbl homology (DH) domain important for guanine nucleotide exchange factor catalytic function, all Dbl family proteins contain an adjacent pleckstrin homology (PH) domain that serves to regulate DH domain activity. Although the role of the PH domain in Vav function has been evaluated extensively, its precise role and whether it serves a distinct role in different Vav proteins remain unresolved. Additionally, the precise role of an adjacent cysteine-rich domain (CRD) in regulating DH domain function is also unclear. In this study, we evaluated the contribution of these putative protein-protein or protein-lipid interaction domains to Vav signaling and transforming activity. In contrast to previous observations, we found that the PH domain is critical for Vav transforming activity. Similarly, the CRD was also essential and served a function distinct from that of the PH domain. Although mutation of either domain reduced Vav membrane association, addition of plasma membrane targeting sequences to either the CRD or PH domain mutant proteins did not restore Vav transforming activity. This result contrasts with other Dbl family proteins, where a membrane targeting sequence alone was sufficient to restore the loss of function caused by mutation of the PH domain. Furthermore, green fluorescent protein fusion proteins containing the PH domain or CRD, or both, failed to target to the plasma membrane, suggesting that these two domains also serve regulatory functions independent of promoting membrane localization. Finally, we found that phosphatidylinositol 3-kinase activation may promote Vav membrane association via phosphatidylinositol 3,4,5-triphosphate binding to the PH domain.

One of the major goals of researchers in the field of apoptosis is to understand the molecular mechanisms of the various components of the apoptotic pathways, with the hope to identify targets for novel cancer therapies. The discovery of a TNF-related, apoptosis-inducing ligand, TRAIL, that kills transformed cells with great specificity in vitro, has provided the hope that TRAIL may be used to induce cell death in tumor cells without affecting normal tissues. However, TRAIL signaling is very complex and a clear understanding of its function is necessary before it can be used in cancer therapy. Complexity of TRAIL-induced signaling is apparent from its ubiquitous expression, its ability to interact with five receptors, and its tumor-selective induction of apoptosis. The signaling events that mediate the tumor selectivity of TRAIL-induced apoptosis and the biological functions of each of the TRAIL receptors are not well characterized. This review will focus on the complexity of TRAIL and the role of c-FLIP in mediating TRAIL function.

Vav and Vav2 are members of the Dbl family of proteins that act as guanine nucleotide exchange factors (GEFs) for Rho family proteins. Whereas Vav expression is restricted to cells of hematopoietic origin, Vav2 is widely expressed. Although Vav and Vav2 share highly related structural similarities and high sequence identity in their Dbl homology domains, it has been reported that they are active GEFs with distinct substrate specificities toward Rho family members. Whereas Vav displayed GEF activity for Rac1, Cdc42, RhoA, and RhoG, Vav2 was reported to exhibit GEF activity for RhoA, RhoB, and RhoG but not for Rac1 or Cdc42. Consistent with their distinct substrate targets, it was found that constitutively activated versions of Vav and Vav2 caused distinct transformed phenotypes when expressed in NIH 3T3 cells. In contrast to the previous findings, we found that Vav2 can act as a potent GEF for Cdc42, Rac1, and RhoA in vitro. Furthermore, we found that NH2-terminally truncated and activated Vav and Vav2 caused indistinguishable transforming actions in NIH 3T3 cells that required Cdc42, Rac1, and RhoA function. In addition, like Vav and Rac1, we found that Vav2 activated the Jun NH2-terminal kinase cascade and also caused the formation of lamellipodia and membrane ruffles in NIH 3T3 cells. Finally, Vav2-transformed NIH 3T3 cells showed up-regulated levels of Rac-GTP. We conclude that Vav2 and Vav share overlapping downstream targets and are activators of multiple Rho family proteins. Therefore, Vav2 may mediate the same cellular consequences in nonhematopoietic cells as Vav does in hematopoietic cells.

Upon request from tribal nations, and as part of the Centers for Disease Control and Prevention’s (CDC’s) emergency response, CDC staff provided both remote and on-site assistance to tribes to plan, prepare, and respond to the COVID-19 pandemic. From April 2, 2020, through June 11, 2021, CDC deployed a total of 275 staff to assist 29 tribal nations. CDC staff typically collaborated in multiple work areas including epidemiology and surveillance (86%), contact tracing (76%), infection prevention control (72%), community mitigation (72%), health communication (66%), incident command structure (55%), emergency preparedness (38%), and worker safety (31%). We describe the activities of CDC staff in collaboration with 4 tribal nations, Northern Cheyenne, Hoopa Valley, Shoshone-Bannock, and Oglala Sioux Tribe, to combat COVID-19 and lessons learned from the engagement.

Deletion of the NH2-terminal 65 amino acids of proto-Vav (to form onco-Vav) activates its transforming activity, suggesting that these sequences serve a negative regulatory role in Vav function. However, the precise role of these NH2-terminal sequences and whether additional NH2-terminal sequences are also involved in negative regulation have not been determined. Therefore, we generated additional NH2-terminal deletion mutants of proto-Vav that lack the NH2-terminal 127, 168, or 186 amino acids, and assessed their abilities to cause focus formation in NIH 3T3 cells and to activate different signaling pathways. Since Vav mutants lacking 168 or 186 NH2-terminal residues showed a several 100-fold greater focus forming activity than that seen with deletion of 65 residues, residues spanning 66 to 187 also contribute significantly to negative regulation of Vav transforming activity. The increase in Vav transforming activity correlated with the activation of the c-Jun, Elk-1, and NF-κB transcription factors, as well as increased transcription from the cyclin D1 promoter. Tyrosine 174 is a key site of phosphorylation by Lck in vitroand Lck-mediated phosphorylation has been shown to be essential for proto-Vav GEF function in vitro. However, we found that an NH2-terminal Vav deletion mutant lacking this tyrosine residue (ΔN-186 Vav) retained the ability to be phosphorylated by Lckin vivoand Lck still caused enhancement of ΔN-186 Vav signaling and transforming activity. Thus, Lck can stimulate Vav via a mechanism that does not involve Tyr174or removal of NH2-terminal regulatory activity. Finally, we found that NH2-terminal deletion enhanced the degree of Vav association with the membrane-containing particulate fraction and that an isolated NH2-terminal fragment (residues 1–186) could impair ΔN-186 Vav signaling. Taken together, these observations suggest that the NH2terminus may serve as a negative regulator of Vav by intramolecular interaction with COOH-terminal sequences to modulate efficient membrane association.

Dbs was identified initially as a transforming protein and is a member of the Dbl family of proteins (>20 mammalian members). Here we show that Dbs, like its rat homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs transforming activity was blocked by specific inhibitors of RhoA and Cdc42 function, demonstrating the importance of these small GTPases in Dbs-mediated growth deregulation. Although Dbs transformation was dependent upon the structural integrity of its pleckstrin homology (PH) domain, replacement of the PH domain with a membrane localization signal restored transforming activity. Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside. Both Dbs and Dbl activate multiple signaling pathways that include activation of the Elk-1, Jun, and NF-κB transcription factors and stimulation of transcription from the cyclin D1 promoter. We found that Elk-1 and NF-κB, but not Jun, activation was necessary for Dbl and Dbs transformation. Finally, we have observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in a NF-κB-dependent manner. Previous studies have dissociated actin cytoskeletal activity from the transforming potential of RhoA and Cdc42. These observations, when taken together with those of the present study, suggest that altered gene expression, and not actin reorganization, is the critical mediator of Dbl and Rho family protein transformation.

ABSTRACTDbs was identified initially as a transforming protein and is a member of the Dbl family of proteins (>20 mammalian members). Here we show that Dbs, like its rat homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs transforming activity was blocked by specific inhibitors of RhoA and Cdc42 function, demonstrating the importance of these small GTPases in Dbs-mediated growth deregulation. Although Dbs transformation was dependent upon the structural integrity of its pleckstrin homology (PH) domain, replacement of the PH domain with a membrane localization signal restored transforming activity. Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside. Both Dbs and Dbl activate multiple signaling pathways that include activation of the Elk-1, Jun, and NF-?B transcription factors and stimulation of transcription from the cyclin D1 promoter. We found that Elk-1 and NF-?B, but not Jun, activation was necessary for Dbl and Dbs transformation. Finally, we have observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in a NF-?B-dependent manner. Previous studies have dissociated actin cytoskeletal activity from the transforming potential of RhoA and Cdc42. These observations, when taken together with those of the present study, suggest that altered gene expression, and not actin reorganization, is the critical mediator of Dbl and Rho family protein transformation.

ABSTRACTActivated forms of different Rho family members (CDC42, Rac1, RhoA, RhoB, and RhoG) have been shown to transform NIH 3T3 cells as well as contribute to Ras transformation. Rho family guanine nucleotide exchange factors (GEFs) (also known as Dbl family proteins) that activate CDC42, Rac1, and RhoA also demonstrate oncogenic potential. The faciogenital dysplasia gene product, FGD1, is a Dbl family member that has recently been shown to function as a CDC42-specific GEF. Mutations within the FGD1locus cosegregate with faciogenital dysplasia, a multisystemic disorder resulting in extensive growth impairments throughout the skeletal and urogenital systems. Here we demonstrate that FGD1 expression is sufficient to cause tumorigenic transformation of NIH 3T3 fibroblasts. Although both FGD1 and constitutively activated CDC42 cooperated with Raf and showed synergistic focus-forming activity, both quantitative and qualitative differences in their functions were seen. FGD1 and CDC42 also activated common nuclear signaling pathways. However, whereas both showed comparable activation of c-Jun, CDC42 showed stronger activation of serum response factor and FGD1 was consistently a better activator of Elk-1. Although coexpression of FGD1 with specific inhibitors of CDC42 function demonstrated the dependence of FGD1 signaling activity on CDC42 function, FGD1 signaling activities were not always consistent with the direct or exclusive stimulation of CDC42 function. In summary, FGD1 and CDC42 signaling and transformation are distinct, thus suggesting that FGD1 may be mediating some of its biological activities through non-CDC42 targets.

ABSTRACTActivated forms of different Rho family members (CDC42, Rac1, RhoA, RhoB, and RhoG) have been shown to transform NIH 3T3 cells as well as contribute to Ras transformation. Rho family guanine nucleotide exchange factors (GEFs) (also known as Dbl family proteins) that activate CDC42, Rac1, and RhoA also demonstrate oncogenic potential. The faciogenital dysplasia gene product, FGD1, is a Dbl family member that has recently been shown to function as a CDC42-specific GEF. Mutations within the FGD1locus cosegregate with faciogenital dysplasia, a multisystemic disorder resulting in extensive growth impairments throughout the skeletal and urogenital systems. Here we demonstrate that FGD1 expression is sufficient to cause tumorigenic transformation of NIH 3T3 fibroblasts. Although both FGD1 and constitutively activated CDC42 cooperated with Raf and showed synergistic focus-forming activity, both quantitative and qualitative differences in their functions were seen. FGD1 and CDC42 also activated common nuclear signaling pathways. However, whereas both showed comparable activation of c-Jun, CDC42 showed stronger activation of serum response factor and FGD1 was consistently a better activator of Elk-1. Although coexpression of FGD1 with specific inhibitors of CDC42 function demonstrated the dependence of FGD1 signaling activity on CDC42 function, FGD1 signaling activities were not always consistent with the direct or exclusive stimulation of CDC42 function. In summary, FGD1 and CDC42 signaling and transformation are distinct, thus suggesting that FGD1 may be mediating some of its biological activities through non-CDC42 targets.

We investigated an outbreak of infection in 10 patients with blood cultures positive for B. cepacia. All patients had indwelling intravenous catheters. Though we did not identify the source of the organism, our findings support the hypothesis that cross-contamination of multidose medications through the use of the same needle and syringe was a contributing factor.

Ortel: Instrumentation Laboratories: Consultancy.

Ortel: Instrumentation Laboratories: Consultancy. Raskob:Bayer Healthcare: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Tetherex: Consultancy; Novartis: Consultancy; Anthos: Consultancy; Janssen R&D, LLC: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; BMS: Consultancy, Honoraria; Portola: Consultancy; Eli Lilly: Consultancy.

Introduction: Venous thromboembolism (VTE), defined as deep vein thrombosis (DVT), pulmonary embolism (PE), or both, represents a major cause of morbidity and mortality in patients with cancer. VTE is the second leading cause of death in patients with cancer, after cancer itself, in the United States. Previous studies have suggested differences by race in the occurrence of VTE among cancer patients. The purpose of this study was to investigate clinical differences in black and white patients with VTE and cancer.

Introduction