A Link between Meiotic Prophase Progression and Crossover Control

During meiosis, most organisms ensure that homologous chromosomes undergo at least one exchange of DNA, or crossover, to link chromosomes together and accomplish proper segregation. How each chromosome receives a minimum of one crossover is unknown. During early meiosis in Caenorhabditis elegans and many other species, chromosomes adopt a polarized organization within the nucleus, which normally disappears upon completion of homolog synapsis. Mutations that impair synapsis even between a single pair of chromosomes in C. elegans delay this nuclear reorganization. We quantified this delay by developing a classification scheme for discrete stages of meiosis. Immunofluorescence localization of RAD-51 protein revealed that delayed meiotic cells also contained persistent recombination intermediates. Through genetic analysis, we found that this cytological delay in meiotic progression requires double-strand breaks and the function of the crossover-promoting heteroduplex HIM-14 (Msh4) and MSH-5. Failure of X chromosome synapsis also resulted in impaired crossover control on autosomes, which may result from greater numbers and persistence of recombination intermediates in the delayed nuclei. We conclude that maturation of recombination events on chromosomes promotes meiotic progression, and is coupled to the regulation of crossover number and placement. Our results have broad implications for the interpretation of meiotic mutants, as we have shown that asynapsis of a single chromosome pair can exert global effects on meiotic progression and recombination frequency

Plk1 regulates mitotic Aurora A function through βTrCP-dependent degradation of hBora

Polo-like kinase 1 (Plk1) and Aurora A play key roles in centrosome maturation, spindle assembly, and chromosome segregation during cell division. Here we show that the functions of these kinases during early mitosis are coordinated through Bora, a partner of Aurora A first identified in Drosophila. Depletion of human Bora (hBora) results in spindle defects, accompanied by increased spindle recruitment of Aurora A and its partner TPX2. Conversely, hBora overexpression induces mislocalization of Aurora A and monopolar spindle formation, reminiscent of the phenotype seen in Plk1-depleted cells. Indeed, Plk1 regulates hBora. Following Cdk1-dependent recruitment, Plk1 triggers hBora destruction by phosphorylating a recognition site for \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{SCF}}^{{\text{ $ \beta $ - TrCP}}}$$\end{document}. Plk1 depletion or inhibition results in a massive accumulation of hBora, concomitant with displacement of Aurora A from spindle poles and impaired centrosome maturation, but remarkably, co-depletion of hBora partially restores Aurora A localization and bipolar spindle formation. This suggests that Plk1 controls Aurora A localization and function by regulating cellular levels of hBora

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Thoracic lymphadenopathy due to vascular transformation of lymph node sinuses associated with upper limb edema in a chronic hemodialysis patient with congestive heart failure

BACKGROUND: Vascular transformation of lymph node sinuses (VTLS) is a rare disorder characterized by transformation of lymph node sinuses into endothelium-lined capillary-like channels. This phenomenon was originally discovered by accident whilst examining regional lymph nodes draining cancer. However, it has been found in association with other conditions associated with lympho venous congestion and distension, such as congestive heart failure (CHF) or even lymphoadenopathy alone. CASE REPORT: We describe the clinical case of a male dialysis patient with CHF (secondary to ischemic-hypertensive cardiac failure) who developed gross edema of the upper left limb on the arteriovenous fistula (AVF) side. Edema appeared within a month after carotid endoarteriectomy following approximately twenty years of chronic hemodialysis. Doppler ultrasound with other investigations showed that subclavian and upper cava veins were patent, but revealed many enlarged lymph nodes in the upper left thorax and in the left axilla. Suspicion of lymphoproliferative disease or metastatic involvement was raised and a lymph node biopsy was performed, revealing VTLS. Bone marrow biopsy and abdominal tomographies showed no mass or a proliferative disorder. Based on a hypothesis of an association between upper limb edema and ipsilateral AVF, the AVF was tied. The upper limb edema decreased dramatically within weeks, whilst RRT was continued by means of a central venous catheter. However, a few months later the patient's condition worsened; he developed relapsing pleural effusions and eventually died. Post-mortem examination revealed severe ischemic-calcific cardiopathy and showed that major thoracic and brachial vessels were patent whilst most thoracic and hilar lymph nodes showed VTLS and fibrosis. CONCLUSIONS: We believe that in our patient CHF was the primary cause of thoracic adenomegaly and that CHF, together with venous hypertension at the left fistula's arm, caused ipsilateral limb edema. Thus, adenomegaly due to VTLS could represent an accompanying feature even in upper limb edema in chronic hemodialysis patients. To our knowledge, this is the first report of such an association. In our patient months were "lost" because we thought that limb edema was secondary to the adenomegaly. It is important that clinicians working in dialysis units are aware that when upper limb edema is present, adenomegaly might just be an accompanying symptom, especially in case of concomitant diagnosis of CHF

Asenapine increases nitric oxide release and protects porcine coronary artery endothelial cells against peroxidation.

Changes in endothelial function and peroxidation could play a significant role in the pathophysiology of cardiovascular disease in psychiatric patients. In particular, endothelial nitric oxide (NO) could either exert a beneficial or detrimental effect depending on the involvement of NO synthase (NOS) subtype. Therefore, we planned to examine the effects of asenapine on NO release and protection against oxidative stress in porcine coronary endothelial cells (CEC). The Griess system and Western blot were used for NO detection and to examine changes in protein activation and expression. In addition, cell oxidative/antioxidant status and mitochondrial membrane potential were measured by specific fluorescent dyes. Asenapine caused a concentration-dependent increase of NO production (p<0.05) by the involvement of cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), phospholipase C (PLC), \u3b22-adrenoceptor-related pathway, Akt, extracellular-signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK). Furthermore, asenapine protected CEC against oxidative stress by preventing reactive oxygen species production and glutathione reduction, mitochondrial membrane potential collapse and apoptosis, and by modulation of the inducible NOS (iNOS). In conclusion, in CEC asenapine induced eNOS-dependent NO production through an intracellular signaling leading to Akt, ERK1/2 and p38MAPK activation. Moreover, asenapine protected CEC against oxidative stress by modulation of antioxidant system, apoptosis, cell survival signaling and mitochondria functioning

Clonal selection of a novel deleterious TP53 somatic mutation discovered in ctDNA of a KIT/PDGFRA wild-type gastrointestinal stromal tumor resistant to imatinib

The standard of care for the first-line treatment of advanced gastrointestinal stromal tumor (GIST) is represented by imatinib, which is given daily at a standard dosage until tumor progression. Resistance to imatinib commonly occurs through the clonal selection of genetic mutations in the tumor DNA, and an increase in imatinib dosage was demonstrated to be efficacious to overcome imatinib resistance. Wild-type GISTs, which do not display KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations, are usually primarily insensitive to imatinib and tend to rapidly relapse in course of treatment. Here we report the case of a 53-year-old male patient with gastric GIST who primarily did not respond to imatinib and that, despite the administration of an increased imatinib dose, led to patient death. By using a deep next-generation sequencing barcodeaware approach, we analyzed a panel of actionable cancer-related genes in the patient cfDNA to investigate somatic changes responsible for imatinib resistance. We identified, in two serial circulating tumor DNA (ctDNA) samples, a sharp increase in the allele frequency of a never described TP53 mutation (c.560-7_560-2delCTCTTAinsT) located in a splice acceptor site and responsible for a protein loss of function. The same TP53 mutation was retrospectively identified in the primary tumor by digital droplet PCR at a subclonal frequency (0.1%). The mutation was detected at a very high allelic frequency (99%) in the metastatic hepatic lesion, suggesting a rapid clonal selection of the mutation during tumor progression. Imatinib plasma concentration at steady state was above the threshold of 760 ng/ml reported in the literature for the minimum efficacious concentration. The de novo TP53 (c.560-7_560-2delCTCTTAinsT) mutation was in silico predicted to be associated with an aberrant RNA splicing and with an aggressive phenotype which might have contributed to a rapid disease spread despite the administration of an increased imatinib dosage. This result underlies the need of a better investigation upon the role of TP53 in the pathogenesis of GISTs and sustains the use of next-generation sequencing (NGS) in cfDNA for the identification of novel genetic markers in wild-type GISTs

Psychotherapy with music intervention improves anxiety, depression and the redox status in breast cancer patients undergoing radiotherapy: A randomized controlled clinical trial

The aim of this study was to assess the effects of psychotherapy with music intervention (PMI) on anxiety, depression, redox status, and inflammation in breast cancer patients undergoing radiotherapy (RT). This monocentric randomized clinical trial recruited 60 patients who had a breast cancer operation and were undergoing postoperative RT. Eligible patients were randomized (1:1) in two groups: the control group (CG) received treatment as usual (n = 30), i.e., RT alone; the intervention group (PMI) received RT and psychotherapy with music intervention (n = 30), which was delivered in a group setting. Five patients were excluded after randomization. Assessments were performed at baseline (T0), at the end of RT (T1), and three months after the end of RT (T2). The main objectives of the study were the assessment of anxiety/depression, plasma glutathione (GSH), and thiobarbituric acid reactive substances (TBARS) in the two arms of the study. Our findings revealed a positive effect of PMI on anxiety, depression, resilience, and quality of life. Furthermore, a positive effect of PMI on redox status was found for the first time. Thus, in the PMI group, we found a significant increase of GSH (mean change 2.2 95%, CI 0.7 to 3.7) and a significant reduction of TBARS (mean change 121.1 95%, CI 121.8 to 120.3) at T2 vs. T

Protective effects elicited by levosimendan against liver ischemia/reperfusion injury in anesthetized rats

As in other organs, oxidative stress-induced injury and cell death may result from free oxygen radicals-dependent mechanisms and alterations in signal transduction pathways leading to apoptosis. Among new suggested therapies against injuries caused by oxidative stress, the use of levosimendan has been reported to be quite promising. In the present study we aimed to examine the protective effects of levosimendan against liver oxidative stress in anesthetized rats and to analyze the involvement of mitochondrial ATP-dependent K (mitoKATP ) channels and nitric oxide (NO). In 50 anesthetized rats, liver ischemia/reperfusion was performed by non-traumatic portal occlusion. In some animals, levosimendan was infused into the portal vein at the onset of reperfusion whereas other rats received vehicle only. Moreover, in some rats, levosimendan was given after intra-portal L-N?-nitro-arginine-methyl-esthere (L-NAME), or 5-hydroxydecanoate (5HD). Portal vein blood flow was measured and blood samples were taken for transaminases, thiobarbituric acid reactive substances (TBARS) and gluthatione (GSH) determination, whereas liver biopsy samples were used for Bax, Caspase 9, Akt and endothelial NOS (eNOS) activation through Western blot. Also, Caspase 3 activity was measured. In rats, ischemia/reperfusion caused an increase of apoptotic markers, transaminases and TBARS, and a decrease of GSH and of Akt activation. Levosimendan administration was able to counteract oxidative damages and apoptosis in a dose-dependent way and to increase GSH, Akt and eNOS activation. All effects of levosimendan were abolished by pre-treatment with L-NAME and 5HD. The results of the present study have shown that levosimendan can exert protection against liver ischemic damages through mechanisms related to NO production and mitoKATP channels function. These data open interesting perspectives for the use of levosimendan in hepatic surgery and transplantation