Breast cancer treatment and adverse cardiac events: what are the molecular mechanisms?

Cardiotoxicity associated with breast cancer treatment is an important concern in the oncology clinic. Different types of anti-cancer therapies have recorded high rates of cardiac dysfunction in treated patients. Cardiac dysfunction linked to anthracyclines--one of the most common conventional chemotherapies--has extensively been described and several mechanisms have been proposed, although their mode of action is not fully understood even in cancer cells. The mediation of cardiac damage by reactive oxygen species stress is a recent hypothesis that has attracted a lot of interest, since it might explain the tissue-specific toxic effects of anthracyclines in the heart. Regarding molecular targeted tyrosine kinase inhibitors used in patients with human epidermal growth factor receptor type 2+ tumours (e.g., trastuzumab, lapatinib), it is the blockage of survival pathways required for a normal heart development and function that seems to lead to cardiac pathology. Both types of breast cancer treatment appear to trigger cardiotoxicity synergically, being patients under adjuvant therapy closely monitored. Given the complex nature of heart failure and of the pathways altered by anti-cancer drugs, global gene expression regulation is key in the heart disease process. MicroRNAs have been demonstrated to be small molecules with big roles as essential gene expression modulators. The great potential of microRNAs as biomarkers in the cardio-oncology field needs to be further explored before new microRNA-based diagnostic and therapeutic tools can be developed.     

Do circannual rhythm of cortisol and testosterone interfere with variations induced by other events?

OBJECTIVE: Cortisol and testosterone are two hormones whose levels may vary in response to sports or occupational events. We wondered if the circannual rhythm of these hormones could have an influence on such responses or whether changes can always be ascribed to a single cause. METHOD: For cortisol, we conducted a cross-sectional study among 102 adult men (mean age 42 years) using saliva samples taken one half hour after awakening. The values were combined over three-month periods corresponding to the four seasons. For testosterone, conclusions were drawn from data reported in the literature. RESULTS: The mean annual cortisol level was 14.36+/-0.44 nmol/l. There was no significant difference between average and peak values nor between maximal and minimal values. For testosterone, there have been a limited number of studies and it is unclear whether there is a seasonal change. In any case, the amplitude of variations is weak (9.7% between peak and annual average), which is partly ascribable to individual and interindividual variability. CONCLUSION: We conclude that there is no seasonal (or circannual) rhythm in cortisol levels to a degree which could interfere with effects resulting from other events. For testosterone, the circannual rhythm may account for 10% of the variation.     

Embolic events caused by aortic thrombi: An underestimated entity?

Stroke and other thromboembolic events are mainly caused by emboli from heart, aorta and other arteries. In this paper we describe a group of 5 middle-aged patients suffering from emboli caused by large thrombi in the aorta. Since the development of giant thrombi under high flow conditions in the aorta is a pathophysiological process which is not well understood, a model of flow distribution by numerically simulating the Navier–Stokes equation for an incompressible fluid was generated. This model simulated how such thrombi may develop in the aorta. We hypothesize that large thrombi issuing from the aortic vessel wall represent a underestimated entity in middleaged persons and are probably overlooked as the cause of stroke or other embolic events in some cases.     

Mitosis–meiosis and sperm–oocyte fate decisions are separable regulatory events

Germ cell fate decisions are poorly understood, despite their central role in reproduction. One fundamental question has been whether germ cells are regulated to enter the meiotic cell cycle (i.e., mitosis–meiosis decision) and to be sperm or oocyte (i.e., sperm–oocyte decision) through one or two cell fate choices. If a single decision is used, a male-specific or female-specific meiotic entry would lead necessarily toward spermatogenesis or oogenesis, respectively. If two distinct decisions are used, meiotic entry should be separable from specification as sperm or oocyte. Here, we investigate the relationship of these two decisions with tools uniquely available in the nematode Caenorhabditis elegans. Specifically, we used a temperature-sensitive Notch allele to drive germ-line stem cells into the meiotic cell cycle, followed by chemical inhibition of the Ras/ERK pathway to reprogram the sperm–oocyte decision. We found that germ cells already in meiotic prophase can nonetheless be sexually transformed from a spermatogenic to an oogenic fate. This finding cleanly uncouples the mitosis–meiosis decision from the sperm–oocyte decision. In addition, we show that chemical reprogramming occurs in a germ-line region where germ cells normally transition from the mitotic to the meiotic cell cycle and that it dramatically changes the abundance of key sperm–oocyte fate regulators in meiotic germ cells. We conclude that the C. elegans mitosis–meiosis and sperm–oocyte decisions are separable regulatory events and suggest that this fundamental conclusion will hold true for germ cells throughout the animal kingdom.Germ cells make two major cell fate choices. One is a cell cycle decision and one is a sexual fate decision. During the course of their development, germ cells are regulated to transition from the mitotic to the meiotic cell cycle, and they are regulated to produce sperm in males or oocytes in females. A fundamental question in the germ cell field has been whether the mitosis–meiosis and sperm–oocyte decisions represent one or two regulatory events (1). If a single decision, germ cells might decide between male-specific meiotic entry leading to spermatogenesis or female-specific meiotic entry leading to oogenesis. If two distinct decisions, germ cells would be regulated to enter the meiotic cell cycle in a way that is separable from their sexual fate decision. Major progress has been made in understanding regulation of the mitosis–meiosis decision (2), but the sperm–oocyte decision has been less tractable in most organisms. Here we investigate the relationship between the mitosis–meiosis and sperm–oocyte decisions in the nematode Caenorhabditis elegans, in which molecular regulators of the two decisions can be manipulated independently.C. elegans adults exist as XO males or self-fertile XX hermaphrodites. Males produce sperm continuously; hermaphrodites make oocytes continuously in adults, after generating a limited number of sperm as larvae. In both sexes, the adult germ-line tissue is organized linearly along its distal to proximal axis: at the distal end, germ cells in the mitotic cell cycle occupy the “mitotic zone” (MZ); more proximally, germ cells enter the meiotic cell cycle and progress through meiotic prophase; germ cells terminally differentiate as sperm or oocytes at the proximal end (Fig. 1A). Germ cells move from distal to proximal as they progressively mature.Open in a separate windowFig. 1.The mitosis–meiosis and sperm–oocyte cell fate decisions are separable. (A) Organization of WT C. elegans adult germ line. The stem cell niche (red) resides at the distal end; mitotic germ cells (gray) occupy the MZ; germ cells then enter the meiotic cell cycle and progress through early meiotic prophase (aqua-colored crescents) in the TZ and through pachytene (blue) in the pachytene zone (PZ). XX adult hermaphrodites make only oocytes (green). (B) Distal end of glp-1(ts) adult gonad. Germ cells are in the mitotic cell cycle at permissive temperature (15 °C) but enter the meiotic cell cycle when shifted to restrictive temperature (25 °C). (C) XX puf-8;lip-1 mutants make only sperm (purple), but treatment with the MEK inhibitor U0126 induces functional oocytes. (D) Experimental design to test separation of mitosis–meiosis and sperm–oocyte decisions. glp-1(ts);puf-8;lip-1 triple mutants are shifted to restrictive temperature (25 °C) to drive all germ cells into meiotic prophase (aqua-colored crescents); then U0126 or a DMSO solvent control is added, and germ lines are scored 24 h later for sperm or oocytes. (E, G, H, and J–L) Extruded gonads outlined in light blue; white arrowhead marks distal end; white dashed lines mark zone boundaries; small white arrow marks most distal meiotic prophase crescent. (Scale bars, 10 μm.) (E) At 15 °C (Upper), EdU labeling reveals S-phase nuclei in MZ, and DAPI shows meiotic prophase crescents, beginning at row 10. After 8 h at 25 °C, EdU incorporation ceases and crescent-shaped nuclei extend to distal end (Lower). (F) EdU incorporation as a function of time at 25 °C. Few S-phase cells remain at 6 h, and none remain at 8 h. Plot shows means ± SEM. (G) At 15 °C, the MZ lacks HIM-3 and crescents begin at row 10. (H) At 6 h after the shift to 25 °C, the MZ has been replaced by HIM-3⁺ meiotic cells that form crescents. (I) Percentage of HIM-3⁺ cells present in the distal germ line (i.e., MZ plus distal TZ) as a function of time shifted to 25 °C; light blue marks when all germ cells have entered the meiotic cell cycle. Points show means ± SEM. (J–L) Gamete sex can be reprogrammed from sperm to oocyte in meiotic germ cells. Sperm were visualized with sperm-specific marker SP56 (purple arrowheads); oocytes were seen with oocyte-specific marker OMA-2 (green arrowheads). % oo+, percentage of oocyte-positive animals. (J) Animals shifted to 25 °C for 6 h (U0126, 42% oocyte-positive animals, n = 12; DMSO, 0% oocyte-positive animals, n = 17); (K) animals shifted to 25 °C for 8 h (U0126, 52% oocyte-positive animals, n = 27 germ lines; DMSO, 0% oocyte-positive animals, n = 20); and (L) animals shifted to 25 °C for 10 h (U0126, 44% oocyte-positive animals, n = 32; DMSO, 4% oocyte-positive animals, n = 27 germ lines).Regulators of the mitosis–meiosis decision have been identified and can be manipulated in C. elegans (3). The stem cell niche at the distal end (Fig. 1A, red) employs Notch signaling to maintain germ cells in the mitotic cell cycle and prevent meiotic entry. Without the C. elegans Notch receptor GLP-1 (Germ Line Proliferation-1), all mitotic germ cells enter the meiotic cell cycle and differentiate. A glp-1 ts (temperature-sensitive) mutant maintains the MZ at permissive temperature (15 °C), but, at the restrictive temperature (25 °C), all germ cells (including germ-line stem cells) enter the meiotic cell cycle (Fig. 1B). Therefore, glp-1(ts) mutants provide a powerful tool for manipulating the mitosis–meiosis decision in adults.Regulators of the sperm–oocyte decision have also been identified and can be manipulated in C. elegans (3, 4). C. elegans germ cell sex relies on somatic signaling plus germ cell-specific sperm–oocyte fate regulators that respond to the somatic signals (3, 5). By manipulating sperm–oocyte fate regulators with temperature-sensitive mutants, RNA-mediated interference, or small molecule intervention, adults making sperm can be transformed to make oocytes without affecting somatic sex (e.g., refs. 4, 6, 7). Such a transformation from sperm to oocyte production can be induced in WT XO adult males or in XX adult hermaphrodites with an aberrantly masculinized germ line. Adults making oocytes can also be transformed to make sperm, again without affecting somatic sex (8). Germ-line sexual transformation does not appear to convert mature sperm into oocytes or vice versa, but instead switches the adult tissue from production of a gamete of one sex (e.g., sperm) into production of the other (e.g., oocyte).One sperm–oocyte fate regulator is the C. elegans homologue of ERK/MAPK, called MPK-1 (9). We previously found that chemical inhibitors of Ras/ERK signaling can reprogram adults from sperm to oocyte production when applied in a puf-8;lip-1 sensitized mutant background (4) (Fig. 1C). XX puf-8;lip-1 adult germ lines make sperm instead of oocytes, likely because of the dual loss of the puf-8 oocyte fate regulator (10) and the lip-1 dual specificity phosphatase, which leads to hyperactivation of the MPK-1/ERK sperm fate regulator (9, 11). Importantly, this chemically induced oogenesis generates functional oocytes that support embryogenesis (4). Treatment with Ras/ERK inhibitors therefore provides a method to manipulate the sperm–oocyte decision quickly (mature oocytes are seen 24 h after treatment) and independently of a temperature shift.In this study, we manipulate the mitosis–meiosis and sperm–oocyte decisions independently and find that they can be uncoupled: germ cells in meiotic prophase can be sexually transformed from a spermatogenic to an oogenic cell fate. We also find that the sperm-to-oocyte fate chemical reprogramming occurs in a region in the distal germ line where cells transition from the mitotic to the meiotic cell cycle, and that it is accompanied by dramatic changes in key sperm–oocyte fate regulators. Together these results provide compelling evidence that the mitosis–meiosis and sperm–oocyte decisions are separable regulatory events.     

Cardiovascular events and atherosclerosis in patients with type 2 diabetes and impaired glucose tolerance: What are the medical treatments to prevent cardiovascular events in such patients?

Type 2 diabetes mellitus and impaired glucose tolerance (IGT) significantly induce advanced coronary artery disease and systemic atherosclerosis. Thus, type 2 diabetes mellitus and IGT are traditional risk factors of cardiovascular disease. In contrast, acute coronary syndrome is frequently caused by the rupture of coronary atherosclerotic plaques, which reduces patients’ quality of life and might result in death. To date, many trials have sought to identify ways to determine the coronary plaque volume and its vulnerability, and many studies have shown that some specific antihyperglycemic agents might prevent coronary or carotid plaque progression, decrease plaque volume, induce plaque stability, and improve clinical outcomes in patients with type 2 diabetes mellitus and IGT. This article reviews the following: (i) the association between coronary or carotid plaques and abnormal glucose tolerance, including type 2 diabetes mellitus; and (ii) the effects of oral antihyperglycemic drugs to improve clinical outcomes and stabilize atherosclerotic plaques in patients with type 2 diabetes mellitus and IGT.     

δ13CO2 Excretion and Expression of Dyspeptic Symptoms in Patients Evaluated for Helicobacter pylori Infection by [13C] Urea Breath Test

Previous studies showed that either the urease activity possessed by H. pylori and the bacterial load may influence the results of the [¹³C] urea breath test. However, the correlation between urease activity and dyspepsia is unclear. The aim of our study was to evaluate whether the urease activity of the gastroduodenal tract may influence the severity of dyspeptic symptoms. In all, 2520 dyspeptic patients (1109 men, 1411 women; mean age 47 ± 16 years) without gastroesophageal reflux disease, diabetes, vascular disorders, liver and biliary tract diseases, and tumors of the gastrointestinal tract and with a normal appearing abdominal ultrasonography were enrolled. All these patients underwent a [¹³C] urea breath test and filled out a questionnaire on dyspeptic symptoms. Subjects were divided in five different groups according to delta over baseline (DOB) values (group 1 < 3.5, group 2 = 3.5–6; group 3 = 6.1–11, group 4 = 11.1–23, group 5 > 23.1). The prevalence and intensity of dyspeptic symptoms were compared among groups. In all, 1688 patients (67%, 928 females and 760 males; mean age 48 ± 15 years) were H. pylori-positive. The chi-squared test and analysis of variance showed increase of frequency and intensity of each dyspeptic symptom according to DOB values. In conclusion, Dyspepsia may parallel gastric urease activity. However, whether higher DOB values are related to higher bacterial load or, alternatively, to the presence of particular H. pylori strains able to produce larger amounts of urease is uncertain.     

Who are the candidates for the treatment by raloxifen ?

There is evidence that raloxifene prevents vertebral fracture and it improves bone metabolism in patients with osteoporosis to the normal pre-menopausal level. Therefore, it is suitable to use for osteoporotic patients with adequate physical activity and those improvable by exercise. Patients who will be treated by anabolic agents are also good candidates for the treatment of raloxifene.     

Malaria vaccines: where are we and where are we going?

Malaria is still killing over one million people each year and its incidence is increasing. The need for an effective vaccine is greater than ever. A major difficulty with vaccine research is that the malaria parasite presents thousands of antigens to the human immune system that vary throughout its life cycle. Identifying those that may prove to be vaccine targets is complicated and time consuming. Most vaccines are targeted at individual stages of the malaria life cycle, although it is likely that only the development of a multistage vaccine will offer complete protection to both visitors to, and residents of, a malaria-endemic area. With the development of a successful vaccine other issues such as cost, distribution, education, and compliance will have to be addressed. This review describes some of the current vaccine candidates for immunising against malaria.     

Negative life events and age-related decline in mastery: are older adults more vulnerable to the control-eroding effect of stress?

OBJECTIVES: The purpose of this study was to see if exposure to life events influences age-related decline in control. METHODS: The data came from a large, nationally representative sample of Canadians aged 18 and older (n = 17, 291). We examined the principal research question by testing for an interaction between age, life events, and mastery using linear regression, both cross-sectionally and over time. RESULTS: Similar to previous work, there was a nonlinear association between age and mastery. The data suggested that exposure to life events was associated with lower levels of perceived control at any age, but that the impact of stress exposure was stronger in older adults. This effect was also evident for change in mastery over time. DISCUSSION: The findings from this study suggest that exposure to life events is an important, yet overlooked, determinant of age-related decline in control. Loss of personal and social resources may be the reason older adults appear more vulnerable to the negative effects of stress.     

Alcoholic hepatitis: How far are we and where are we going?

The burden of alcoholic liver disease continues to be a major public health problem worldwide. The spectrum of disease ranges from fatty liver to cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis (AH) is a type of acute-on-chronic liver failure and the most severe form of alcoholic liver disease. Severe AH carries a poor short-term prognosis and its management is still challenging, with scarce advances in the last decades. Corticosteroids are still the first line of therapy in severe cases. Unfortunately, many patients do not respond and novel targeted therapies are urgently needed. Liver transplantation has shown extraordinary results in non-responders to corticosteroids however; its applicability is very low. This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis.