Direct oral anticoagulants versus warfarin in patients with single or double antibody-positive antiphospholipid syndrome.

Warfarin is recognized as the standard treatment for thrombotic antiphospholipid syndrome (APS); however, direct oral anticoagulants (DOACs) represent appealing therapeutic alternatives given their lack of monitoring and limited drug interactions. A few randomized controlled trials comparing rivaroxaban with warfarin showed an increased risk of recurrent thromboembolism, specifically arterial thrombosis, in patients with high risk forms of APS such as those that are triple antibody positive. We conducted a single-center, retrospective cohort study of all patients within our health system from 2015 to 2020 with a diagnosis of APS (single or double antibody positive) and history of venous thromboembolism. We sought to compare the proportion of patients with a recurrent thrombosis when prescribed a DOAC versus warfarin. Among 96 patients included, 57 were prescribed warfarin and 39 were prescribed a DOAC (90% rivaroxaban). The proportion of patients with a recurrent thromboembolism was almost three times higher in the DOAC group (15.4%) compared to the warfarin group (5.3%), although this was not statistically significant (p = 0.15). Major bleeding was not different between groups. Our findings suggest that rivaroxaban may pose an increased risk for recurrent thromboembolism in low risk APS patients that are single or double-antibody positive compared to warfarin. Results of our study should be cautiously applied to DOACs besides rivaroxaban given their small representation in this study.

Acute Resistance Exercise Performance Is Negatively Impacted by Prior Aerobic Endurance Exercise.

Ratamess, NA, Kang, J, Porfido, TM, Ismaili, CP, Selamie, SN, Williams, BD, Kuper, JD, Bush, JA, and Faigenbaum, AD. Acute resistance exercise performance is negatively impacted by prior aerobic endurance exercise. J Strength Cond Res 30(10): 2667-2681, 2016-The purpose of the present study was to examine acute resistance exercise (RE) performance after 4 different aerobic endurance (AE) protocols. Eleven healthy, resistance-trained men (21.0 ± 1.2 years) performed a control RE protocol and 4 RE protocols 10 minutes after different AE protocols in random sequence. The RE protocol consisted of 5 exercises (high pull, squat, bench press, deadlift, and push press) performed for 3 sets of 6-10 repetitions with 70-80% of one repetition-maximum (1RM) with 3-minute rest intervals in between sets. The AE protocols consisted of treadmill running at velocities corresponding to: (a) 60% of their V[Combining Dot Above]O2 reserve (V[Combining Dot Above]O2R) for 45 minutes (P1); (b) 75% of their V[Combining Dot Above]O2R for 20 minutes (P2); (c) 90-100% of V[Combining Dot Above]O2R in 3-minute intervals (1:1 ratio) for 5 sets (P3); and (d) 75% of V[Combining Dot Above]O2R (4.5 mph) uphill (6-9% grade) for 20 minutes (P4). Completed repetitions, average power and velocity, heart rate (HR), and ratings of perceived exertion (RPE) were assessed each set. Protocols P1-P4 resulted in 9.1-18.6% fewer total repetitions performed compared with the control RE protocol with the squat experiencing the greatest reduction. Average power and velocity were significantly reduced for the high pull, squat, and bench press after most AE protocols. Ratings of perceived exertion values for the high pull and squat were significantly higher in P1-P4 compared with control. Heart rate was significantly higher during RE after P1-P4 compared with control by 4.3-5.5%. These results indicate acute RE performance is significantly compromised in healthy men after AE exercise of different type, intensity, and duration with largest reductions observed after high-intensity interval exercise.

"Our Generation Is Trying to Break Some of That Resistance to Emotions"-A Mixed-Methods Pilot Examination of Tuning in to Kids for Black Parents of Preschoolers in the United States.

BACKGROUND: A growing body of literature examines the utility of emotion-focused parenting programs, as behaviorally based programs currently dominate the parenting literature. Few of those studies examine differences in how Black parents may benefit. This mixed-methods pilot study examined preliminary fidelity, efficacy, and acceptability of Tuning in to Kids (TIK), an emotion-focused parenting program targeting parenting practices and children's emotion regulation through a strengths-based approach. METHODS: Pre, post, and one-month follow-up measurements were collected from 21 parents in the United States who were randomly assigned to a treatment (i.e., TIK) or waitlist control group. They were assessed across several self-report parent measures (parental emotion regulation, emotion socialization parenting practices and beliefs) and parent-report of children's social-emotional competence. Parents in the TIK group completed interviews to further understand their experience participating in the intervention. RESULTS: Descriptive analyses showed general improvements and positive change in parenting practices, beliefs, parental emotion regulation, and children's self-regulation. Large effect sizes indicate reductions of parents emotion dismissing and distressed reactions to children's negative emotions. TIK was overall rated as a highly acceptable intervention. Parent interviews offer essential information to provide context to Black parents' experiences utilizing TIK as well as themes related to challenges in raising Black children with self-regulation difficulties. CONCLUSIONS: Overall, these preliminary mixed-methods outcomes suggest that TIK is a promising parenting program to improve Black parents' emotion regulation, emotion coaching beliefs and positive parenting practices. Further research is needed to investigate the effectiveness of TIK and other emotion-focused parenting programs with Black parents and assess the necessity of future cultural adaptations.

Diabetes: how to manage patients experiencing hypoglycaemia.

Hypoglycaemia is a complication associated with the management of both type 1 and type 2 diabetes. Despite newer technologies to help minimize the risk of hypoglycaemia, it remains a barrier for some patients to achieve optimal glycaemic control. In this review, the definitions and risk factors for hypoglycaemia will be briefly discussed and an in-depth review of the management for a conscious or unconscious patient in the outpatient and inpatient settings is provided. Rapid-acting glucose is the preferred treatment for a conscious patient regardless of the setting. For an unconscious patient, glucagon is preferred if the patient does not have intravenous (IV) access and dextrose can be used for patients with IV access. Until recently, there was only one formulation of glucagon, which had limitations due to the multiple steps required for reconstitution prior to administration in an emergency setting. This review also discusses the different glucagon formulations currently available for the management of hypoglycaemia.

The expression of Tousled kinases in CaP cell lines and its relation to radiation response and DSB repair.

BACKGROUND: The Tousled-like kinases (TLKs) function in processes of chromatin assembly, including replication, transcription, repair, and chromosome segregation. TLK1/1B interacts specifically with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, and with Rad9, a protein involved in DNA repair, and these interactions are believed to be responsible for the action of TLKs in double-strand break repair and radioprotection. METHODS: Western blotting and RT-PCR were used to analyze the expression of TLK1, TLK1B, and TLK2 in a panel of prostate cancer (CaP) cell lines. The pattern of radiotolerance in the cell lines was analyzed in parallel. DU145 and PC-3 cells were also probed with assays utilizing transfected plasmids that could be cleaved in vivo with adeno-expressed HO nuclease to assess the potential contribution of TLK1/1B in DSB repair. RESULTS: This is the first report of TLKs' expression in a panel of CaP cell lines and their relationship to radioresistance. Furthermore, expression of TLK1B in non-expressing PC-3 cells rendered them highly resistant to radiation, and conversely, knockdown to TLK1/1B in expressing DU145 reduced their radiotolerance. CONCLUSIONS: TLKs appear to be intimately linked to the pattern of resistance to DNA damage, and specifically DSBs, a finding that was not reported before for any cell lines, and certainly not systematically for human prostate cell lines.

TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro.

TIMP-1 (Tissue inhibitor of matrix metalloproteinase-1) is typically associated with inhibition of matrix metalloproteinases (MMP) induced invasion. However, TIMP-1 is overexpressed in many malignancies and is associated with poor prognosis in breast cancer. The mechanisms by which TIMP-1 promotes tumorigenesis are unclear. Reduced levels of TIMP-1 mediated by shRNA in MDA-MB-231 breast cancer cells had no effect on cellular physiology in vitro or tumor growth in SCID mice compared to vector control MDA-MB-231 cells. However, overexpression of TIMP-1 in MDA-MB-231 cells resulted in inhibition of cell invasion and enhanced phosphorylation of p38 MAPK and AKT in vitro. Additionally, treatment of parental MDA-MB-231 cells with purified TIMP-1 protein led to activation of p38 MAPK and MKK 3/6. cDNA array analysis demonstrated that high expression of TIMP-1 in MDA-MB-231 cells resulted in alterations in expression of approximately 200 genes, 1.5 fold or greater compared to vector control cells (P < 0.1). Real-time RT-PCR confirmed changes in expression of several genes associated with cancer progression including DAPK1, FGFR4 and MAPK13. In vivo, high TIMP-1 expression induced tumor growth in SCID mice compared to vector control cells and increased tumor vessel density. Affymetrix array analysis of vector control and TIMP-1 MDA-MB-231 xenograft tumors revealed that TIMP-1 altered expression of approximately 600 genes in vivo, including MMP1, MMP13, S100A14, S100P, Rab25 and ID4. These combined observations suggest that the effects of TIMP-1 differ significantly in a 2-D environment compared to the 3-D environment and that TIMP-1 stimulates tumor growth.

Intermediate filament protein synemin contributes to the migratory properties of astrocytoma cells by influencing the dynamics of the actin cytoskeleton.

We have shown previously that, in astrocytoma cells, synemin is present at the leading edge, an unusual localization for an intermediate filament (IF) protein. Here, we report that synemin down-regulation with specific small hairpin RNAs (shRNAs) sharply decreased the migration of astrocytoma cells. The presence of synemin at the leading edge also correlated with a high migratory potential, as shown by comparing astrocytoma cells to carcinoma cells without synemin at the leading edge. Synemin-silenced astrocytoma cells were smaller and spread more slowly than controls. In addition, synemin silencing reduced proliferation without increasing apoptosis. The adhesion to substratum and distribution of vinculin in focal contacts of synemin-silenced astrocytoma cells were similar to those of controls. Synemin-silenced cells, however, exhibited a reduction in the amount of filamentous (F) -actin and of alpha-actinin, but not of vinculin, associated with F-actin. Altogether, these results demonstrate that synemin is important for the malignant behavior of astrocytoma cells and that it contributes to the high motility of these cells by modulating the dynamics of alpha-actinin and actin.

A review of sotagliflozin for use in type 1 diabetes.

Type 1 diabetes is a challenging disease that is largely managed with the use of insulin. The risk of hypoglycemia, side effects of weight gain, and high glucose variability associated with insulin use have prompted researchers to explore additional therapies to treat this condition. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications that lower glucose in type 2 diabetes patients independent of insulin action, and have been studied for use in the type 1 diabetes population. Sotagliflozin is an SGLT2 inhibitor that demonstrates a unique binding affinity for the SGLT1 receptor. A total of three phase III clinical trials (inTandem1, inTandem2, and inTandem3) were conducted to evaluate the safety and efficacy of sotagliflozin in type 1 diabetes. A modest hemoglobin A1C reduction of 0.3-0.4% was observed, with secondary benefits of reduced glucose variability, reduced insulin dosage, and positive weight loss effects. Overall there was a reduction in the risk of severe hypoglycemia with sotagliflozin, but a higher rate of ketone formation and risk of diabetic ketoacidosis was observed, along with increased mycotic infections and volume depletion effects.

A dominant negative mutant of TLK1 causes chromosome missegregation and aneuploidy in normal breast epithelial cells.

BACKGROUND: In Arabidopsis thaliana, the gene Tousled encodes a protein kinase of unknown function, but mutations in the gene lead to flowering and leaf morphology defects. We have recently cloned a mammalian Tousled-Like Kinase (TLK1B) and found that it phosphorylates specifically histone H3, in vitro and in vivo. We now report the effects that overexpression of a kinase-dead mutant of TLK1B mediates in a normal diploid cell line. RESULTS: Expression of a kinase-dead mutant resulted in reduction of phosphorylated histone H3, which could have consequences in mitotic segregation of chromosomes. When analyzed by FACS and microscopy, these cells displayed high chromosome number instability and aneuploidy. This phenomenon was accompanied by less condensed chromosomes at mitosis; failure of a number of chromosomes to align properly on the metaphase plate; failure of some chromosomes to attach to microtubules; and the occasional presentation of two bipolar spindles. We also used a different method (siRNA) to reduce the level of endogenous TLK1, but in this case, the main result was a strong block of cell cycle progression suggesting that TLK1 may also play a role in progression from G1. This block in S phase progression could also offer a different explanation of some of the later mitotic defects. CONCLUSIONS: TLK1 has a function important for proper chromosome segregation and maintenance of diploid cells at mitosis in mammalian cells that could be mediated by reduced phosphorylation of histone H3 and condensation of chromosomes, although other explanations to the phenotype are possible.

Dendritic cell based PSMA immunotherapy for prostate cancer using a CD40-targeted adenovirus vector.

Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.

The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells.

PURPOSE: Activation of the c-Met and epidermal growth factor receptors (EGFR) promotes the growth and survival of non-small cell lung cancer (NSCLC). Specific receptor antagonists have shown efficacy in the clinic, but tumors often become resistant to these therapies. We investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to inhibit cell proliferation, and c-Met receptor and EGFR kinase activation in several NSCLC cell lines. EXPERIMENTAL DESIGN: NSCLC cell lines with variable sensitivity to the EGFR antagonist erlotinib were studied. Cell growth was evaluated using proliferation and colony formation assays. Kinase activation was assessed via Western blot analysis. Experiments were conducted with EGCG, the EGFR antagonist erlotinib, and the c-Met inhibitor SU11274. The antagonists were also tested in a xenograft model using SCID mice. RESULTS: EGCG inhibited cell proliferation in erlotinib-sensitive and -resistant cell lines, including those with c-Met overexpression, and acquired resistance to erlotinib. The combination of erlotinib and EGCG resulted in greater inhibition of cell proliferation and colony formation than either agent alone. EGCG also completely inhibited ligand-induced c-Met phosphorylation and partially inhibited EGFR phosphorylation. The triple combination of EGCG/erlotinib/SU11274 resulted in a greater inhibition of proliferation than EGCG with erlotinib. Finally, the combination of EGCG and erlotinib significantly slowed the growth rate of H460 xenografts. CONCLUSION: EGCG is a potent inhibitor of cell proliferation, independent of EGFR inhibition, in several NSCLC cell lines, including those resistant to both EGFR kinase inhibitors and those overexpressing c-Met. Therefore, EGCG might be a useful agent to study as an adjunct to other anticancer agents.

Endometroid adenocarcinoma of the uterus with cardiac metastasis. A case report and six-year follow-up.

BACKGROUND: There are few reported cases of cardiac metastasis associated with endometrial cancer (EC) and no reports of long-term survival. We report a case of EC presenting with metastasis to the right ventricle resulting in right heart failure. CASE: A 61-year-old woman presented with a 10-day history of increasing pedal edema. Two-dimensional echocardiography (2DE) revealed a large echogenic mass within the right ventricle. She underwent exploration of the heart with debulking which revealed a metastatic poorly differentiated epithelial tumor. Further work-up with a dilation and curettage revealed a poorly differentiated EC. A total abdominal hysterectomy with pelvic and para-aortic lymhadenectomy was performed with disease confined to the uterus/cervix. She then received cardiac radiation with concurrent cisplatin, followed by pegylated liposomal doxorubicin (PLD) for 1 year and remained disease free through 6.5 years of follow-up. At 6.8 years, she died of a constrictive pericarditis with no evidence of disease. CONCLUSION: While experience with cardiac metastasis for gynecologic malignancy is limited, it appears that multimodality therapy affected a durable complete response however late complications of cardiac radiation ultimately lead to death.