Tissue plasminogen activator-based clot busting: Controlled delivery approaches.

Cardiovascular diseases are the leading cause of death worldwide. Thrombosis, the formation of blood clot (thrombus) in the circulatory system obstructing the blood flow, is one of the main causes behind various ischemic arterial syndromes such as ischemic stroke and myocardial infarction, as well as vein syndromes such as deep vein thrombosis, and consequently, pulmonary emboli. Several thrombolytic agents have been developed for treating thrombosis, the most common being tissue plasminogen activator (tPA), administrated systemically or locally via IV infusion directly proximal to the thrombus, with the aim of restoring and improving the blood flow. TPA triggers the dissolution of thrombi by inducing the conversion of plasminogen to protease plasmin followed by fibrin digestion that eventually leads to clot lysis. Although tPA provides powerful thrombolytic activity, it has many shortcomings, including poor pharmacokinetic profiles, impairment of the reestablishment of normal coronary flow, and impairment of hemostasis, leading to life-threatening bleeding consequences. The bleeding consequence is ascribed to the ability of tPA to circulate throughout the body and therefore can lysis all blood clots in the circulation system, even the good ones that prevent the bleeding and promote injury repair. This review provides an overview of the different delivery approaches for tPA including: liposomes, ultrasound-triggered thrombolysis, anti-fibrin antibody-targeted tPA, camouflaged-tPA, tpA-loaded microcarriers, and nano-modulated delivery approaches

MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network

Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2

Investigating the causal role of MRE11A p.E506* in breast and ovarian cancer

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway. However, whether MRE11A is a true predisposition gene for HBOC is still questionable. We determined to investigate this notion by dissecting the molecular genetics of the c.1516G > T;p.E506* truncating MRE11A variant, that we pinpointed in two unrelated French-Canadian (FC) HBOC patients. We performed a case-control study for the variant in ~ 2500 breast, ovarian, and endometrial cancer patients from the founder FC population of Quebec. Furthermore, we looked for the presence of second somatic alterations in the MRE11A gene in the tumors of the carriers. In summary, these investigations suggested that the identified variant is not associated with an increased risk of developing breast or ovarian cancer. We finally performed a systematic review for all the previously reported MRE11A variants in breast and ovarian cancer. We found that MRE11A germline variants annotated as pathogenic on ClinVar often lacked evidence for such classification, hence misleading the clinical management for affected patients. In summary, our report suggests the lack of clinical utility of MRE11A testing in HBOC, at least in the White/Caucasian populations

Potential predictors for successful misoprostol treatment for early pregnancy failure: Clinical and color Doppler imaging study

Objective: To identify the clinical characteristics and features of color Doppler imaging related to successful misoprostol treatment for early pregnancy failure. Design: Prospective observational study. Main outcome measures: Factors related to successful misoprostol treatment for early pregnancy failure. Materials and methods: Four groups of women with early pregnancy failure (missed, anembryonic and incomplete miscarriage) were included in the study. The first group included 159 cases, 73 were presenting with active vaginal bleeding and/or localized abdominal colic in the 24 h preceding misoprostol administration and 86 cases were not presenting with these symptoms. The parity of all participants was ⩾2. The second group included 143 cases that did not present with vaginal bleeding and/or abdominal colic. The parity was 0–1 in 66 cases and ⩾2 in 77 cases. The third group included 34 cases of missed miscarriage and 22 cases of anembryonic pregnancy presenting with active vaginal bleeding and/or localized abdominal colic and the parity was 0–1.The fourth group included 172 women, blood flow was detected by color Doppler imaging in the trophoblastic tissue in 90 cases and was absent in 82 cases. All participants in this group did not present with vaginal bleeding and/or localized abdominal colic and their parity was ⩾2. All participants in the four groups were given 800 μg vaginal misoprostol on day 1 of treatment. If the miscarriage was not complete on day 3 the same dose was repeated. On day 8 they were submitted to dilatation and evacuation if miscarriage was not complete. Miscarriage was considered complete when no gestation sac was detected in the uterine cavity on transvaginal ultrasonography. Results: First group: the success rate of the two doses of misoprostol, when active vaginal bleeding and/or localized abdominal colic were present, was 94.52% (69 out of 73 cases). In absence of these symptoms the success rate was 75.58% (65 out of 86 cases). The difference was statistically (p = 0.0241) significant. Second group: the success rate of the two doses of misoprostol, when parity was 0–1, was 98.48% (65 cases out of 66). When parity was ⩾2 the success rate was 85.71% (60 cases out of 77). The difference was statistically (p = 0.0442) significant. Third group: the success rate of the first dose of misoprostol for missed miscarriage was 97.05%, 33 cases out of 34 cases and 100% for anembryonic miscarriage, 22 out of 22 cases. One case of missed miscarriage needed a second dose of misoprostol to complete the miscarriage. Fourth group: the success rate of the two doses of misoprostol, when blood flow was detected in the IVS of missed miscarriage and anembryonic pregnancy, was 100.0% (62 out of 62 cases). When blood flow was not detected in the IVS the success rate was 83.92% (47 out of 56 cases). The difference was statistically (p = 0.0422) significant. When blood flow (vascularity) was detected in the trophoblastic tissue of incomplete miscarriage the success rate was 75.0% (21 out of 28 cases) but when no blood flow (vascularity) was detected the success rate was 100% (26 out of 26 cases). The difference was statistically (p = 0.0331) significant. Conclusions: The potential predictors for successful misoprostol treatment for early pregnancy failure may be one or more of the following: 1. Active vaginal bleeding and/or localized abdominal colic in the 24 h preceding misoprostol administration. 2. Nulliparity or low parity not more than 1. 3. Blood flow in the presumed IVS of missed miscarriage or anembryonic pregnancy and absence of blood flow (vascularity) in trophoblastic tissue of incomplete miscarriage. Women, with early pregnancy failure, presenting with a combination of active vaginal bleeding and/or abdominal colic and parity 0–1, the success rate of the first-dose of vaginal misoprostol (800 μg) may reach >97% in missed miscarriage and 100% with anembryonic pregnancy

Maternal serum concentrations of angiogenic and antiangiogenic factors in threatened miscarriage at 7–12 weeks’ gestation and the risk of adverse pregnancy outcomes

Objective: To assess the ability of first trimester maternal serum (FTMS) soluble Fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio in the first trimester threatened miscarriage (FTTM) to predict fetal loss in early pregnancy and adverse pregnancy outcomes when pregnancy continued to ⩾30 weeks to start suitable antenatal care as early as possible. Design: A case control prospective cross-sectional study. Material and methods: 320 cases of TM, 7–12 weeks’ gestation and 320 normal controls 7–12 weeks’ gestation without vaginal bleeding and other manifestations of FTTM and delivered at ⩾30 weeks’ gestation were enrolled in the study. All were primigravidae. Estimation of FTMS sFlt-1 and PlGF in the first trimester of TM and controls by enzyme-like immunosorbent assay (ELISA) and follow up of them till delivery were done. Adverse pregnancy outcomes encountered were gestational hypertension (GH), preeclampsia (PE), intrauterine growth restriction (IUGR), abruptio placentae, spontaneous preterm labor (PTL), placenta previa, preterm premature rupture of membranes (PPROM) and retained placenta. Results: All adverse pregnancy outcomes were significantly (P 74.6 (cut-off point) predicted these adverse pregnancy outcomes with sensitivity 88.70%, specificity 95.40, positive predictive value 90.16% and negative predictive value 94.68% – adverse pregnancy outcomes not related to placental impairment as PLT >34 weeks’ gestation, PPROM, placenta previa and retained placenta were not predicted by sFlt-1/PlGF ratio because in these conditions FTMS concentration of these factors were normal. Conclusions: 1-Adverse outcomes late in pregnancy (⩾30 weeks’ gestation) were more common in FTTM. 2-Diminished FTMS concentration of sFlt-1 and PlGF as well as sFlt-1/PlGF ratio 74.6 may predict development of adverse outcomes characterized by impaired placentation. 4-Adverse pregnancy outcomes not related to impaired placentation were associated with normal FTMS concentration of sFlt-1 and PlGF and were not predicted by sFlt-1/PlGF ratio

MRN Complex and Cancer Risk: Old Bottles, New Wine

The MRN complex, composed of MRE11A, RAD50, and NBN, mediates vital molecular functions to maintain genomic stability and hence protect against related disorders. Germline mutations in the MRN genes predispose to three different syndromes: ataxia-telangiectasia-like disorder (MRE11A deficiency), Nijmegen breakage syndrome (NBS; NBN deficiency), and NBS-like disorder (RAD50 deficiency). The potential cancer component of these syndromes in addition to the close physical and functional proximity of the MRN complex to BRCA1 has promoted the MRN genes as candidate risk genes for developing breast cancer. This notion has been challenged by independent large-scale population-based studies. Despite having their two-decade old candidacy as breast cancer genes close to being refuted, it has recently been reported that the MRN genes rise to have potential new roles in clonal hematopoiesis. In this article, we discuss the history and current status of MRN genes' clinical utility in breast cancer and then focus on their recently uncovered and less understood roles in clonal hematopoiesis that likely predispose to health-related disorders such as hematologic malignancies and/or cardiovascular morbid events