Glioblastoma Therapy: Past, Present and Future.

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

Ifosfamide-induced nephrotoxicity in oncological patients.

INTRODUCTION: Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of various neoplasms. Its main adverse effects include renal damage. AREAS COVERED: A comprehensive review was conducted, including 100 articles from the Scielo, Scopus, and EMBASE databases. Ifosfamide-induced nephrotoxicity is attributed to its toxic metabolites, such as acrolein and chloroacetaldehyde, which cause mitochondrial damage and oxidative stress in renal tubular cells. Literature review found a 29-year average age with no gender predominance and a mortality of 13%. Currently, no fully effective strategy exists for preventing ifosfamide-induced nephrotoxicity; however, hydration, forced diuresis, and other interventions are employed to limit renal damage. Long-term renal function monitoring is essential for patients treated with ifosfamide. EXPERT OPINION: Ifosfamide remains essential in neoplasm treatment, but nephrotoxicity, often compounded by coadministered drugs, poses diagnostic challenges. Preventive strategies are lacking, necessitating further research. Identifying timely risk factors can mitigate renal damage, and a multidisciplinary approach manages established nephrotoxicity. Emerging therapies may reduce ifosfamide induced nephrotoxicity.

Ifosfamide is a type of chemotherapy used to treat different types of cancers. However, one of its main side effects is kidney damage. Researchers reviewed 100 articles from medical databases to understand how ifosfamide affects the kidneys. The kidney damage is caused by harmful substances produced when ifosfamide is broken down in the body. These substances can harm the cells in the kidneys. Studies have shown that 13% of the patients treated with ifosfamide can die. Currently, there is no perfect way to prevent kidney damage from ifosfamide, but doctors try to protect the kidneys by giving patients plenty of fluids and using other treatments, so it's important for patients who receive ifosfamide to have their kidney function checked regularly. Although ifosfamide is effective against cancer, its potential kidney side effects should be carefully considered by doctors when deciding on the best treatment for each patient.

Thyroid dysfunction and female infertility. A comprehensive review.

INTRODUCTION: Female infertility is defined as the inability to achieve pregnancy following one year of consistent, unprotected sexual intercourse. Among the various endocrine factors contributing to this complex issue, thyroid dysfunction assumes a pivotal and noteworthy role. METHODS: A narrative review, encompassing 134 articles up to 2023, was conducted utilizing the PubMed/Medline, EMBASE, and Scielo databases. The primary focus of this review was to investigate the effects of thyroid dysfunction on female infertility. RESULTS: Thyroid disorders exert a significant influence on folliculogenesis, fertilization, and implantation processes. Thyroid autoimmunity, although associated with diminished ovarian reserve, does not typically necessitate levothyroxine therapy. On the other hand, both subclinical and overt hypothyroidism often require levothyroxine treatment to enhance fertility and optimize obstetric outcomes. Hyperthyroidism warrants prompt intervention due to its heightened risk of miscarriage. Furthermore, thyroid dysfunction exerts notable effects on assisted reproductive technologies, underscoring the importance of achieving euthyroidism prior to ovarian stimulation. CONCLUSION: Women presenting with thyroid dysfunction must undergo meticulous and individualized assessments since fertility outcomes, whether achieved through natural conception or assisted reproductive technologies, can be significantly influenced by thyroid-related factors.

Endocrine factors associated with infertility in women: an updated review.

INTRODUCTION: Infertility is defined as the inability to conceive after unprotected sexual intercourse for at least 12 consecutive months. Our objective is to present an updated narrative review on the endocrine causes of infertility in women. AREAS COVERED: A comprehensive review was conducted using Scielo, Scopus, and EMBASE databases, comprising 245 articles. The pathophysiology of infertility in women was described, including endocrinopathies such as hypothalamic amenorrhea, hyperprolactinemia, polycystic ovary syndrome, primary ovarian insufficiency, obesity, thyroid dysfunction, and adrenal disorders. The diagnostic approach was outlined, emphasizing the necessity of hormonal studies and ovarian response assessments. Additionally, the treatment plan was presented, commencing with non-pharmacological interventions, encompassing the adoption of a Mediterranean diet, vitamin supplementation, moderate exercise, and maintaining a healthy weight. Subsequently, pharmacological treatment was discussed, focusing on the management of associated endocrine disorders and ovulatory dysfunction. EXPERT OPINION: This comprehensive review highlights the impact of endocrine disorders on fertility in women, providing diagnostic and therapeutic algorithms. Despite remaining knowledge gaps that hinder more effective treatments, ongoing research and advancements show promise for improved fertility success rates within the next five years. Enhanced comprehension of the pathophysiology behind endocrine causes and the progress in genetic research will facilitate the delivery of personalized treatments, thus enhancing fertility rates.

Diabetic neuropathy: Past, present, and future.

Background: A sedentary lifestyle and an unhealthy diet have considerably increased the incidence of diabetes mellitus worldwide in recent decades, which has generated a high rate of associated chronic complications. Methods: A narrative review was performed in MEDLINE, EMBASES and SciELO databases, including 162 articles. Results: Diabetic neuropathy (DN) is the most common of these complications, mainly producing two types of involvement: sensorimotor neuropathy, whose most common form is symmetric distal polyneuropathy, and autonomic neuropathies, affecting the cardiovascular, gastrointestinal, and urogenital system. Although hyperglycemia is the main metabolic alteration involved in its genesis, the presents of obesity, dyslipidemia, arterial hypertension, and smoking, play an additional role in its appearance. In the pathophysiology, three main phenomena stand out: oxidative stress, the formation of advanced glycosylation end-products, and microvasculature damage. Diagnosis is clinical, and it is recommended to use a 10 g monofilament and a 128 Hz tuning fork as screening tools. Glycemic control and non-pharmacological interventions constitute the mainstay of DN treatment, although there are currently investigations in antioxidant therapies, in addition to pain management. Conclusions: Diabetes mellitus causes damage to peripheral nerves, being the most common form of this, distal symmetric polyneuropathy. Control of glycemia and comorbidities contribute to prevent, postpone, and reduce its severity. Pharmacological interventions are intended to relieve pain.

Neural Stem Cells as Potential Glioblastoma Cells of Origin.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults and it remains incurable. These tumors are very heterogeneous, resistant to cytotoxic therapies, and they show high rates of invasiveness. Therefore, patients face poor prognosis, and the survival rates remain very low. Previous research states that GBM contains a cell population with stem cell characteristics called glioma stem cells (GSCs). These cells are able to self-renew and regenerate the tumor and, therefore, they are partly responsible for the observed resistance to therapies and tumor recurrence. Recent data indicate that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells of origin of GBM, that is, the cell type acquiring the initial tumorigenic mutation. The involvement of SVZ-NSCs is also associated with GBM progression and recurrence. Identifying the cellular origin of GBM is important for the development of early detection techniques and the discovery of early disease markers. In this review, we analyze the SVZ-NSC population as a potential GBM cell of origin, and its potential role for GBM therapies.

Lipschütz acute vulvar ulcer related to COVID-19 vaccination: First case report in South America.

Lipschütz ulcer is a non-sexually transmitted genital lesion of unknown etiology, which presents as a painful vulvar ulcer. Lipschütz ulcers have been described in most continents. This is the first case reported in Peru and South America. We present the case of a 33-year-old female patient with a Lipschütz ulcer after being vaccinated with the second dose of the AstraZeneca COVID-19 vaccine. She reported having had only one sexual partner in her lifetime. Laboratory results were negative for herpes simplex 2, Cytomegalovirus, Toxoplasma gondii, Epstein-Barr virus, and syphilis. The patient received symptomatic treatment. Ten days after the onset, the patient was significantly better during follow-up. This case report displays a potential adverse effect of the AstraZeneca COVID-19 vaccine as a Lipschütz ulcer triggered by the host humoral immune response. However, further research is needed to establish the causal relationship between these two.

La úlcera de Lipschütz es una lesión genital no transmitidas por vía sexual de etiología desconocida, se presenta como una úlcera vulvar muy dolorosa. Las úlceras de Lipschütz se han descrito en la mayoría de los continentes. Este es el primer caso que se reporta en Perú y Sudamérica. En este reporte de caso se presentauna paciente de 33 años con una úlcera de Lipschütz luego de haber sido vacunada con la segunda dosis de la vacuna AstraZeneca COVID-19. Refirió haber tenido una sola pareja sexual a lo largo de su vida. Los resultados de laboratorio fueron negativos para herpes simplex 2, Citomegalovirus, Toxoplasma gondii, virus de Epstein-Barr y sífilis. La paciente recibió tratamiento sintomático. Diez días después, durante el seguimiento, la paciente estaba significativamente mejor. Este reporte de caso expone un potencial efecto adverso de la vacuna AstraZeneca COVID-19, en forma de úlcera de Lipschütz, desencadenado por la respuesta inmune humoral del huésped. Sin embargo, es necesario realizar más investigación para establecer la relación causal entre ambos.

Lipschütz acute vulvar ulcer related to COVID-19 vaccination: First case report in South America / Úlcera vulvar aguda de Lipschütz relacionada con la vacunación por COVID-19: primer caso notificado en Sudamérica

Lipschütz ulcer is a non-sexually transmitted genital lesion of unknown etiology, which presents as a painful vulvar ulcer. Lipschütz ulcers have been described in most continents. This is the first case reported in Peru and South America. We present the case of a 33-year-old female patient with a Lipschütz ulcer after being vaccinated with the second dose of the AstraZeneca COVID-19 vaccine. She reported having had only one sexual partner in her lifetime. Laboratory results were negative for herpes simplex 2, Cytomegalovirus, Toxoplasma gondii, Epstein-Barr virus, and syphilis. The patient received symptomatic treatment. Ten days after the onset, the patient was significantly better during follow-up. This case report displays a potential adverse effect of the AstraZeneca COVID-19 vaccine as a Lipschütz ulcer triggered by the host humoral immune response. However, further research is needed to establish the causal relationship between these two.

La úlcera de Lipschütz es una lesión genital no transmitidas por vía sexual de etiología desconocida, se presenta como una úlcera vulvar muy dolorosa. Las úlceras de Lipschütz se han descrito en la mayoría de los continentes. Este es el primer caso que se reporta en Perú y Sudamérica. En este reporte de caso se presentauna paciente de 33 años con una úlcera de Lipschütz luego de haber sido vacunada con la segunda dosis de la vacuna AstraZeneca COVID-19. Refirió haber tenido una sola pareja sexual a lo largo de su vida. Los resultados de laboratorio fueron negativos para herpes simplex 2, Citomegalovirus, Toxoplasma gondii, virus de Epstein-Barr y sífilis. La paciente recibió tratamiento sintomático. Diez días después, durante el seguimiento, la paciente estaba significativamente mejor. Este reporte de caso expone un potencial efecto adverso de la vacuna AstraZeneca COVID-19, en forma de úlcera de Lipschütz, desencadenado por la respuesta inmune humoral del huésped. Sin embargo, es necesario realizar más investigación para establecer la relación causal entre ambos.

Assessment of hormonal status in male infertility. An update.

BACKGROUND AND AIMS: The prevalence and incidence of infertility are increasing worldwide; they are associated with a significant economic and social impact. Infertility is defined as the inability to achieve pregnancy after 12 months or more of regular unprotected sex. In recent times, the male factor has gained importance and currently it contributes to approximately 50% of infertility cases. Multiple etiologies are stated, such as metabolic, anatomical, genetic or even idiopathic causes; however, the main cause is semen abnormalities. The aim of this manuscript is to provide a complete review of hormonal assessment of male infertility, as well as to review the physiology and pathophysiology related to the male gonadal axis. METHODS: This study is a narrative abstract carried out on basis of systematic bibliographic review, using articles indexed in PubMed/Medline, Scopus, Embase and Scielo, which were published during the last 20 years. RESULTS: The cornerstone of the evaluation of the hormonal status is semen analysis. Clinicians must rule out hypogonadism in those patients who present oligospermia and azoospermia, by determining levels of testosterone and gonadotropins, which provide the functionality status of the hypothalamic-pituitary-testicular axis. Evaluation of the adrenal, thyroid, and lactotroph axis are indicated in those patients with central hypogonadism. CONCLUSIONS: Despite advances in the diagnosis of male infertility, some causes are not fully understood, therefore, it is crucial to perform a timely hormonal evaluation of the male factor in infertile couples, in order to provide adequate treatment and improve fertility rates.

The impact of CD160 deficiency on alloreactive CD8 T cell responses and allograft rejection.

CD160 is a member of the immunoglobulin superfamily with a pattern of expression mainly restricted to cytotoxic cells. To assess the functional relevance of the HVEM/CD160 signaling pathway in allogeneic cytotoxic responses, exon 2 of the CD160 gene was targeted by CRISPR/Cas9 to generate CD160 deficient mice. Next, we evaluated the impact of CD160 deficiency in the course of an alloreactive response. To that aim, parental donor WT (wild-type) or CD160 KO (knock-out) T cells were adoptively transferred into non-irradiated semiallogeneic F1 recipients, in which donor alloreactive CD160 KO CD4 T cells and CD8 T cells clonally expanded less vigorously than in WT T cell counterparts. This differential proliferative response rate at the early phase of T cell expansion influenced the course of CD8 T cell differentiation and the composition of the effector T cell pool that led to a significant decreased of the memory precursor effector cells (MPECs) / short-lived effector cells (SLECs) ratio in CD160 KO CD8 T cells compared to WT CD8 T cells. Despite these differences in T cell proliferation and differentiation, allogeneic MHC class I mismatched (bm1) skin allograft survival in CD160 KO recipients was comparable to that of WT recipients. However, the administration of CTLA-4.Ig showed an enhanced survival trend of bm1 skin allografts in CD160 KO with respect to WT recipients. Finally, CD160 deficient NK cells were as proficient as CD160 WT NK cells in rejecting allogeneic cellular allografts or MHC class I deficient tumor cells. CD160 may represent a CD28 alternative costimulatory molecule for the modulation of allogeneic CD8 T cell responses either in combination with costimulation blockade or by direct targeting of alloreactive CD8 T cells that upregulate CD160 expression in response to alloantigen stimulation.

Complicaciones de la obesidad en niños y adolescentes durante la pandemia de COVID-19: Una revisión narrativa / Complicaciones de la obesidad en niños y adolescentes durante la pandemia de COVID-19: Una revisión narrativa

Introducción: La obesidad en niños y adolescentes ha aumentado exponencialmente en todo el mundo. Asimismo, la pandemia del coronavirus (COVID-19) ha conducido a una mayor tasa de obesidad pediátrica. El exceso de tejido adiposo genera una desregulación de hormonas como adiponectina, ghrelina y leptina, entre otras. Las alteraciones metabólicas pueden ocasionar enfermedad cardiovascular, dislipidemias, hipertensión arterial, diabetes mellitus tipo 2, enfermedad del hígado graso no alcohólico, trastornos del sueño y mayor riesgo de COVID-19 severo. La obesidad tiene diferentes enfoques terapéuticos, como programas conductuales de pérdida de peso, tratamientos farmacológicos y procedimientos quirúrgicos. De esta manera, el diagnóstico y el tratamiento oportuno es importante para disminuir la mortalidad asociada a la obesidad en la población pediátrica.

Introduction: Obesity in children and adolescents has increased exponentially worldwide. Likewise, the coronavirus pandemic (COVID-19) has led to a higher rate of pediatric obesity. Excess adipose tissue leads to dysregulation of hormones such as adiponectin, ghrelin and leptin, among others. Metabolic alterations can lead to cardiovascular disease, dyslipidemias, arterial hypertension, type 2 diabetes mellitus, non-alcoholic fatty liver disease, sleep disorders and increased risk of severe COVID-19. Obesity has different therapeutic approaches, such as behavioral weight loss programs, pharmacological treatments and surgical procedures. Thus, timely diagnosis and treatment is important to decrease obesity-associated mortality in the pediatric population.

Complications of obesity in children and adolescents during covid-19 pandemic: A narrative review

Obesity in children and adolescents has increased exponentially around the world. Furthermore, the COVID-19 pandemic has led to a higher pediatric obesity rate. The excess adipose tissue generates a dysregulation of adiponectin, ghrelin, and leptin, among others. Metabolic alterations can develop cardiovascular disease, dyslipidemias, arterial hypertension, type 2 diabetes mellitus, nonalcoholic fatty liver disease, sleep disorders, and higher risk of COVID-19 severity. Obesity has different therapeutic approaches such as behavioral weight loss programs, pharmacologic treatments, and surgical procedures. Therefore, timely diagnosis and treatment are important to decrease the mortality in obesity among pediatric population.

La obesidad en niños y adolescentes ha aumentado exponencialmente en todo el mundo. Asimismo, la pandemia del coronavirus (COVID-19) ha conducido a una mayor tasa de obesidad pediátrica. El exceso de tejido adiposo genera una desregulación de hormonas como adiponectina, ghrelina y leptina, entre otras. Las alteraciones metabólicas pueden ocasionar enfermedad cardiovascular, dislipidemias, hipertensión arterial, diabetes mellitus tipo 2, enfermedad del hígado graso no alcohólico, trastornos del sueño y mayor riesgo de COVID-19 severo. La obesidad tiene diferentes enfoques terapéuticos, como programas conductuales de pérdida de peso, tratamientos farmacológicos y procedimientos quirúrgicos. De esta manera, el diagnóstico y el tratamiento oportuno es importante para disminuir la mortalidad asociada a la obesidad en la población pediátrica.

Diabetic gastroenteropathy: An underdiagnosed complication.

This article is an extensive review that provides an update on the pathophysiology, symptoms, diagnosis, and treatment of diabetic gastroenteropathy. There is no reported prevalence, but it has been described that patients with type 1 diabetes have a cumulative incidence at 10 years of 5.2%, and type 2 patients, 1%. Also, in the group of type 1 diabetes, it has been observed that women are more likely to present this condition (5.8% vs 3.5%). Many factors are associate with its development (e.g., hyperglycemia, vagal dysfunction, loss of expression of neural nitric oxide synthase in the myenteric plexus, alterations in the Cajal interstitial cell network, and oxidative stress). Gastrointestinal discomfort could be perceived 70% higher in diabetic patients, describing that 25% of diabetic patients experience gastrointestinal symptoms. Diabetic enteropathy could affect any portion of the gastrointestinal tract, but esophageal alterations were described in more than 60% of diabetic patients, also 60% of them present constipation, and 20%, diarrhea. Gastric emptying scintigraphy is useful to evaluate gastroparesis, therefore, gastric retention of more than 60% at 2 h has a sensitivity of 100% and specificity of 20% for diagnosis; however, other studies such as breath tests, with a sensitivity of 89% and a specificity of 80%, or the endoscopic capsule contribute to the diagnosis. There is no cure; however, management must be multidisciplinary, focused on slowing the progression of diabetic gastroenteropathy, reducing symptoms, and restoring function; that includes nutritional recommendation, maintain glucose levels kept below 180 mg/dL, use of prokinetics, anti-emetics; nowadays, it has been special interest in surgical treatment, such as pyloroplasty, also gastric electrical stimulation appears to be another alternative.

Postnatal Catch-Up Growth Programs Telomere Dynamics and Glucose Intolerance in Low Birth Weight Mice.

Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development.

Familial chylomicronemia syndrome-induced acute necrotizing pancreatitis during pregnancy

Abstract Acute pancreatitis is a rare condition in pregnancy, associated with a high mortality rate. Hypertriglyceridemia represents its second most common cause.We present the case of a 38-year-old woman in the 24th week of gestation with a history of hypertriglyceridemia and recurrent episodes of pancreatitis. She was admitted to our hospital with acute pancreatitis due to severe hypertriglyceridemia. She was stabilized and treated with fibrates. Despite her favorable clinical course, she developed a second episode of acute pancreatitis complicated by multi-organ dysfunction and pancreatic necrosis, requiring a necrosectomy. The pregnancy was ended by cesarean section, after which three plasmapheresis sessions were performed. She is currently asymptomatic with stable triglyceride levels. Acute pancreatitis due to hypertriglyceridemia represents a diagnostic and therapeutic challenge in pregnant women, associated with serious maternal and fetal complications. When primary hypertriglyceridemia is suspected, such as familial chylomicronemia syndrome, the most important objective is preventing the onset of pancreatitis.

Familial Chylomicronemia Syndrome-Induced Acute Necrotizing Pancreatitis during Pregnancy.

Acute pancreatitis is a rare condition in pregnancy, associated with a high mortality rate. Hypertriglyceridemia represents its second most common cause. We present the case of a 38-year-old woman in the 24th week of gestation with a history of hypertriglyceridemia and recurrent episodes of pancreatitis. She was admitted to our hospital with acute pancreatitis due to severe hypertriglyceridemia. She was stabilized and treated with fibrates. Despite her favorable clinical course, she developed a second episode of acute pancreatitis complicated by multi-organ dysfunction and pancreatic necrosis, requiring a necrosectomy. The pregnancy was ended by cesarean section, after which three plasmapheresis sessions were performed. She is currently asymptomatic with stable triglyceride levels. Acute pancreatitis due to hypertriglyceridemia represents a diagnostic and therapeutic challenge in pregnant women, associated with serious maternal and fetal complications. When primary hypertriglyceridemia is suspected, such as familial chylomicronemia syndrome, the most important objective is preventing the onset of pancreatitis.