Is seminal nerve growth factor-induced luteinizing hormone release in camelids mediated at the hypothalamus?

In brief: Seminal nerve growth factor induces ovulation in camelids by influencing the secretion of gonadotrophin-releasing hormone (GnRH) into the portal vessels of the pituitary gland. We show that the nerve growth factor-induced release of GnRH is not mediated directly through interaction with hypothalamic neurons. Abstract: Ovulation in camelids is triggered by seminal nerve growth factor (NGF). The mechanism of action of NGF appears to occur via the central nervous system. In this study, we tested the hypothesis that NGF acts in the hypothalamus to induce GnRH release. To determine if NGF-induced ovulation is associated with a rise in NGF concentrations in the cerebrospinal fluid (CSF), llamas were i) mated with an urethrostomized male, ii) mated with intact male, or given intrauterine iii) seminal plasma or i.v.) saline (Experiment 1). To characterize the luteinizing hormone (LH) response after central vs peripheral administration, llamas were treated with saline (negative control) or NGF either by i.v. or intracerebroventricular (ICV) administration (Experiment 2). To determine the role of kisspeptin, the effect of ICV infusion of a kisspeptin receptor antagonist on NGF-induced LH secretion and ovulation was tested in llamas (Experiment 3). In Experiment 1, a surge in circulating concentrations of LH was detected only in llamas mated with an intact male and those given intrauterine seminal plasma, but no changes in CSF concentrations of NGF were detected. In Experiment 2, peripheral administration (i.v.) of NGF induced an LH surge and ovulation, whereas no response was detected after central (ICV) administration. In Experiment 3, the kisspeptin receptor antagonist had no effect on the LH response to NGF. In conclusion, results did not support the hypothesis that NGF-induced ovulation is mediated via a trans-synaptic pathway within the hypothalamus, but rather through a releasing effect on tanycytes at the median eminence.

Granulosa cell tumour in a llama (Lama glama).

Hormonally active tumours are characterized by production and secretion of hormones, irrespective of endogenous feedback mechanisms. An adult llama had exuberant oestrous behaviour, infertility, elevated concentrations of oestradiol and a large ovarian mass. Necropsy revealed the presence of two large abdominal masses, one effacing the right ovary and one in the mesocolon. Considering the clinical and histopathological findings, we conclude that the llama was affected by a granulosa cell tumour. The case suggests that granulosa cell tumours in camelids are hormonally active, and the clinical presentation resembles that of other large animal species. To our knowledge, this is the first case report of an oestrogen-producing, metastatic granulosa cell tumour in a llama.

Palbociclib-Induced Cellular Senescence Is Modulated by the mTOR Complex 1 and Autophagy.

Despite not dividing, senescent cells acquire the ability to synthesize and secrete a plethora of bioactive molecules, a feature known as the senescence-associated secretory phenotype (SASP). In addition, senescent cells often upregulate autophagy, a catalytic process that improves cell viability in stress-challenged cells. Notably, this "senescence-related autophagy" can provide free amino acids for the activation of mTORC1 and the synthesis of SASP components. However, little is known about the functional status of mTORC1 in models of senescence induced by CDK4/6 inhibitors (e.g., Palbociclib), or the effects that the inhibition of mTORC1 or the combined inhibition of mTORC1 and autophagy have on senescence and the SASP. Herein, we examined the effects of mTORC1 inhibition, with or without concomitant autophagy inhibition, on Palbociclib-driven senescent AGS and MCF-7 cells. We also assessed the pro-tumorigenic effects of conditioned media from Palbociclib-driven senescent cells with the inhibition of mTORC1, or with the combined inhibition of mTORC1 and autophagy. We found that Palbociclib-driven senescent cells display a partially reduced activity of mTORC1 accompanied by increased levels of autophagy. Interestingly, further mTORC1 inhibition exacerbated the senescent phenotype, a phenomenon that was reversed upon autophagy inhibition. Finally, the SASP varied upon inhibiting mTORC1, or upon the combined inhibition of mTORC1 and autophagy, generating diverse responses in cell proliferation, invasion, and migration of non-senescent tumorigenic cells. Overall, variations in the SASP of Palbociclib-driven senescent cells with the concomitant inhibition of mTORC1 seem to depend on autophagy.

Duct-like diverticulum at the base of third ventricle tumors: a morphological signature diagnostic of papillary craniopharyngioma.

This study describes and characterizes a narrow, hollow tubular structure, termed as duct-like diverticulum (DV), found specifically at the basal midline of papillary craniopharyngiomas (PCPs) located within the third ventricle (3V). The presence of this structure was systematically investigated on autopsy studies and magnetic resonance imaging (MRI) scans of 3536 craniopharyngioma (CP) cases published in the medical literature from 1911 to 2021, as well as in other twelve 3V tumor categories (n = 1470 cases). A basal DV was observed in a total of 50 PCPs, including two of our own cases. This DV corresponds to a tubular-shaped recess invaginated at the midline bottom of the tumor, following the same angled trajectory as the pituitary stalk. It can be easily seen as a hypointense linear structure on T1- and T2-weighted MRI scans, with two main length types: long DVs (74%), which reach the tumor center, and short DVs (26%), which penetrate the tumor only a few millimeters. The DV sign identifies the papillary CP type with a specificity of 100% and a sensitivity of 33% in the overall CP population. This finding also serves to establish the strictly intra-3V location of the lesion with a 95% specificity and 42% sensitivity among papillary CPs. No similar basal DV was found in adamantinomatous CPs nor among other categories of strictly 3V tumors. Consequently, the presence of a diverticulum in a 3V tumor represents a morphological signature pathognomonic of the papillary type and a valuable sign to reliably define the strictly 3V topography.

A RUL Estimation System from Clustered Run-to-Failure Degradation Signals.

The prognostics and health management disciplines provide an efficient solution to improve a system's durability, taking advantage of its lifespan in functionality before a failure appears. Prognostics are performed to estimate the system or subsystem's remaining useful life (RUL). This estimation can be used as a supply in decision-making within maintenance plans and procedures. This work focuses on prognostics by developing a recurrent neural network and a forecasting method called Prophet to measure the performance quality in RUL estimation. We apply this approach to degradation signals, which do not need to be monotonical. Finally, we test our system using data from new generation telescopes in real-world applications.

[Late-onset hereditary transthyretin amyloidosis with polyneuropathy. Report of one case]. / Polineuropatía por amiloidosis por transtiretina de inicio tardío. Caso clínico.

Hereditary transthyretin amyloidosis is a multisystemic autosomal dominant genetic disorder characterized by progressive distal sensory-motor polyneuropathy or restrictive cardiomyopathy, secondary to amyloid deposits. Its pathogenesis lies in the TTR gene mutation, and the Val50Met mutation is the most frequent. Patients have significant differences in the onset and severity of clinical presentation according to their country of origin. The diagnosis of this pathology is complex, even more in countries where it is not considered endemic. However, early suspicion and management are essential to improve survival and avoid unnecessary diagnostic and therapeutic strategies. We report a 69-year-old woman who presented a sensory-motor polyneuropathy, predominantly sensory, associated with distal neuropathic pain and bilateral vitritis. The history of her Italian father with polyneuropathy of unspecified etiology stood out. A vitreous biopsy identified amyloid substance deposits (congo red positive). These were also confirmed on a superficial peroneal nerve biopsy. During the etiological study of her polyneuropathy, an increased Kappa/Lambda index of 2.55 mg/L stood out. Therefore, light chain amyloidosis was suspected, and chemotherapy treatment was indicated without favorable response. After 10 years of progressive neurological and ophthalmological involvement, a genetic study confirmed the first case of late-onset hereditary transthyretin amyloidosis Val50Met with polyneuropathy in Chile.

Neuroanatomical basis of the nerve growth factor ovulation-induction pathway in llamas†.

The objective of the study was to characterize the anatomical framework and sites of action of the nerve growth factor (NGF)-mediated ovulation-inducing system of llamas. The expression patterns of NGF and its receptors in the hypothalamus of llamas (n = 5) were examined using single and double immunohistochemistry/immunofluorescence. We also compare the expression pattern of the P75 receptor in the hypothalamus of llama and a spontaneous ovulator species (sheep, n = 5). Both NGF receptors (TrkA and P75) were highly expressed in the medial septum and diagonal band of Broca, and populations of TrkA cells were observed in the periventricular and dorsal hypothalamus. Unexpectedly, we found NGF immunoreactive cell bodies with widespread distribution in the hypothalamus but not in areas endowed with NGF receptors. The organum vasculosum of the lamina terminalis (OVLT) and the median eminence displayed immunoreactivity for P75. Double immunofluorescence using vimentin, a marker of tanycytes, confirmed that tanycytes were immunoreactive to P75 in the median eminence and in the OVLT. Additionally, tanycytes were in close association with GnRH and kisspeptin in the arcuate nucleus and median eminence of llamas. The choroid plexus of llamas contained TrkA and NGF immunoreactivity but no P75 immunoreactivity. Results of the present study demonstrate sites of action of NGF in the llama hypothalamus, providing support for the hypothesis of a central effect of NGF in the ovulation-inducing mechanism in llamas.

Hypothalamic involvement and the role of progesterone in the NGF-induced LH surge pathway.

To elucidate the mechanism by which nerve growth factor (NGF) influences the LH secretory pathway in camelids, a series of experiments were done to determine the involvement of the hypothalamus (Experiment 1), the role of GnRH neurons (Experiment 2), and the effect of progesterone (Experiment 3) on the NGF-induced LH surge and ovulation in llamas. In Experiment 1, the declining phase of the NGF-induced LH surge was used to determine if the decline is a result of pituitary depletion or hypothalamic unresponsiveness. Female llamas were treated with NGF and, 7 h later, assigned to three groups and given a second dose of NGF (n = 5), a dose of GnRH (n = 5), or saline (n = 6). The LH response was attenuated after the second dose of NGF vs GnRH. In Experiment 2, Fos expression (marker of neuronal activation) in GnRH neurons was examined in the hypothalamus of llamas after NGF or saline treatment (n = 3 per group). Despite an LH surge in the NGF group but not in the saline group, no differences were detected between groups in Fos/GnRH co-expression. In Experiment 3, llamas in low-, medium-, and high-plasma progesterone groups (n = 4 per group) were treated with NGF. The NGF-induced LH surge did not differ among treatment groups. Results from the present study show that the induction of a preovulatory LH surge by NGF may be controlled by a novel pathway involving GnRH neuro-terminals downstream of the hypothalamus and is independent of progesterone influence.

Coronary artery disease in patients with cancer: challenges and opportunities for improvement.

PURPOSE OF REVIEW: Coronary artery disease (CAD) is a common comorbidity in patients with cancer. We review shared risk factors between the two diseases and cancer treatments that increase the risk of CAD. We also discuss outcomes and management considerations of patients with cancer who develop CAD. RECENT FINDINGS: Several traditional and novel risk factors promote the development of both CAD and cancer. Several cancer treatments further increase the risk of CAD. The presence of cancer is associated with a higher burden of comorbidities and thrombocytopenia, which predisposes patients to higher bleeding risks. Patients with cancer who develop acute coronary syndromes are less likely to receive timely revascularization or appropriate medical therapy, despite evidence showing that receipt of these interventions is associated with substantial benefit. Accordingly, a cancer diagnosis is associated with worse outcomes in patients with CAD. The risk-benefit balance of revascularization is becoming more favorable due to the improving prognosis of many cancers and safer revascularization strategies, including shorter requirements for dual antiplatelet therapy after revascularization. SUMMARY: Several factors increase the complexity of managing CAD in patients with cancer. A multidisciplinary approach is recommended to guide treatment decisions in this high-risk and growing patient group.

Endothelial transmigration of platelets depends on soluble factors released by activated endothelial cells and monocytes.

Cardiovascular diseases (CVDs) remain leading causes of death worldwide. While platelet-mediated thrombus formation following the rupture of an atherosclerotic plaque is one of the key pathophysiologic events in CVDs, the role of platelets in previous or more advanced stages of atherosclerosis is less known. Interestingly, the presence of platelets has been observed at the core of the atherosclerotic plaque.In order to study the conditions necessary for platelets to migrate toward an atherosclerotic lesion, we designed an in vitro co-culture model. Platelets were co-cultured with monocytes in Transwell inserts covered with a confluent endothelium and the number of migrating platelets and/or monocytes was determined under different conditions. Platelets were also exposed to media conditioned obtained from co-cultures prior to migration assays.Here we show that coculturing platelets and monocytes increased platelet transmigration, with a considerable number of transmigrated platelets found not associated to monocytes. Interestingly, conditioned media from platelet-monocyte co-cultures also increased platelet transmigration and aggregation, suggesting the existence of soluble factors secreted by monocytes that enhance the migratory and pro-aggregating capabilities of platelets.We conclude that platelets have the machinery to migrate through an activated endothelium, a response that requires the interaction with secreted factors produce in the context of the interaction with monocytes under atherogenic conditions.