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Chronic venous disease (CVeD) is a rising medical condition characterized by a broad spectrum of disorders in the venous system. Varicose veins (VVs) represent a frequent clinical manifestation of CVeD, particularly in the lower limbs. Prior histopathological studies have defined a set of alterations observed in the venous wall of patients with VVs, affecting their structure and behavior. Metabolic changes in the veins appear to be a critical biological mechanism aiding our understanding of the pathogenesis of CVeD. In this sense, previous studies have identified a potential role of a glycolytic phenotype in the development of different vascular disorders; however, its precise role in CVeD remains to be fully explored. Thus, the aim of the present study was to analyze the gene and protein expression of glucose transporter 1 (GLUT-1) and the glycolytic enzymes PGK-1, ALD, GA3PDH and LDH in the VVs of patients with CVeD (n = 35) in comparison to those expressed in healthy subjects. Our results display enhanced gene and protein expression of GLUT-1, PGK-1, ALD, GA3PDH and LDH in patients with CVeD, suggesting a glycolytic switch of the venous tissue. Greater understanding of the impact of this glycolytic switch in patients with CVeD is required to define a possible pathophysiological role or therapeutic implications of these changes.

Lower limbs venous insufficiency refers to a wide variety of venous disorders grouped by the term of chronic venous disease (CVD). Hemodynamic and hormonal changes related to pregnancy period, may promote the development of CVD affecting approximately 1 in 3 women. It has been shown that the presence of this condition is associated with damage and placental suffering. Thus, taking IGF-1/PAPP-A/STC-2, inflammatory cytokines production, PI3K/Akt and Wnt/ β-catenin pathways as a part of the alterations that occurs in the placenta due to CVD, the aim of this study will be to examine the main components of these pathways. Genic and protein expression of PAPP-A, STC-2, IGF-1, IRS-4 Wnt-1, β-catenin, c-myc, Cyclin D1, IL-4/IL-6 and PI3K/Akt/mTOR pathway will be analysed through RT-qPCR and immunohistochemical techniques in women with CVD (n=62) and pregnant women without this condition (HC) (n=52). PAPP-A, IGF-1, IL-4, IL-6, IRS-4, PI3K, Akt, mTOR, Wnt-1, β-catenin, c-myc and Cyclin D1 expression were found to be increased in women with CVD, whereas STC-2 were decreased in this group, compared to non-affected women. Our study has demonstrated that IGF-1/PAPP-A/STC-2 axis, PI3K/Akt and Wnt/β-catenin pathways, along with c-myc, Cyclin D1 and inflammatory cytokines are altered in placenta women with CVD. These results extent the knowledge that CVD is associated to a placenta damage with abnormal tissue environment and cellular regulation.

Uveal melanoma is the most common type of intraocular cancer with a low mean annual incidence of 5‑10 cases per million. Tumours are located in the choroid (90%), ciliary body (6%) or iris (4%) and of 85% are primary tumours. As in cutaneous melanoma, tumours arise in melanocytes; however, the characteristics of uveal melanoma differ, accounting for 3‑5% of melanocytic cancers. Among the numerous risk factors are age, sex, genetic and phenotypic predisposition, the work environment and dermatological conditions. Management is usually multidisciplinary, including several specialists such as ophthalmologists, oncologists and maxillofacial surgeons, who participate in the diagnosis, treatment and complex follow‑up of these patients, without excluding the management of the immense emotional burden. Clinically, uveal melanoma generates symptoms that depend as much on the affected ocular globe site as on the tumour size. The anatomopathological study of uveal melanoma has recently benefited from developments in molecular biology. In effect, disease classification or staging according to molecular profile is proving useful for the assessment of this type of tumour. Further, the improved knowledge of tumour biology is giving rise to a more targeted approach to diagnosis, prognosis and treatment development; for example, epigenetics driven by microRNAs as a target for disease control. In the present study, the main epidemiological, clinical, physiopathological and molecular features of this disease are reviewed, and the associations among all these factors are discussed.

Pancreatic cancer is a malignancy of rising incidence, especially in developed countries due to causes such as sedentary lifestyles, tobacco smoking and ultraprocessed high fat and high sugar diets, amongst others. It is in fact the 7th cause of cancer-related deaths worldwide, and, in the following years, it is expected to climb upwards to 2nd position, after lung cancer. This is because it may have an asymptomatic course, and when it becomes evident it is in advanced stages, accompanied by metastasis generally. For this reason, survival rates are so low and, even in the few successful cases there is a high possibility of recurrence. Identifying new molecular biomarkers is arising as a highly useful tool for pancreatic cancer clinical management, although much research and work remain to be done in this field. Thus, the present study aims to analyze a series of molecules (IRS-4, Rb1, Ki-67 y COX-2) as candidates for prognosis and survival by immunohistochemistry techniques. Additionally, a 60-month longitudinal surveillance program was conducted, associated with diverse clinical parameters. Kaplan-Meier curves estimating the time of survival according to tumoral expression of those molecules denoted a low cumulative survival rate. Importantly, we observed that high levels of IRS-4 were significantly associated with a bad prognosis of the disease, increasing 160 times the mortality risk. In this way, our research showed a relevant value of these biomarkers in pancreatic cancer patients' survival, opening a pathway for future research areas designed to inhibit these components.

The pathogenesis of chronic venous disorder (CVeD) remains partially understood. A marked wall remodeling has been shown with potential accelerated tissue senescence. We have investigated the expression of peroxisome proliferator-activated receptor (PPAR) isoforms transcription factor EB (TFEB) as regulatory molecules of cellular homeostasis and makers of peroxisomal and lysosomal biogenesis. We have also quantified p16 expression as a cellular senescence marker. In specimens of maior safena vein from 35 CVeD and 27 healthy venous controls (HV), we studied the expression of PPAR-α, PPAR-β/δ, PPAR-γ, TFEB and p16 by RT-qPCR and immunohistochemical techniques. We have demonstrated a reduced gene and protein expression of the PPAR-α and PPAR-β/δ isoform as well as that of TFEB in the venous wall of CVeD patients, suggesting an altered peroxisomal and lysosomal biogenesis associated with an increased cellular senescence shown by increased p16 expression.

The most prevalent diseases of our time, non-communicable diseases (NCDs) (including obesity, type 2 diabetes, cardiovascular diseases and some types of cancer) are rising worldwide. All of them share the condition of an “inflammatory disorder”, with impaired immune functions frequently caused or accompanied by alterations in gut microbiota. These multifactorial maladies also have in common malnutrition related to physiopathology. In this context, diet is the greatest modulator of immune system–microbiota crosstalk, and much interest, and new challenges, are arising in the area of precision nutrition as a way towards treatment and prevention. It is a fact that the westernized diet (WD) is partly responsible for the increased prevalence of NCDs, negatively affecting both gut microbiota and the immune system. Conversely, other nutritional approaches, such as Mediterranean diet (MD), positively influence immune system and gut microbiota, and is proposed not only as a potential tool in the clinical management of different disease conditions, but also for prevention and health promotion globally. Thus, the purpose of this review is to determine the regulatory role of nutritional components of WD and MD in the gut microbiota and immune system interplay, in order to understand, and create awareness of, the influence of diet over both key components.

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (, This study (FIS-PI18/00912) was supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013-2016) and cofinanced by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF) and B2017/BMD-3804 MITIC-CM

Chronic venous disease (CVD) is the response to a series of hemodynamic changes in the venous system and the onset of this disease is often triggered by pregnancy. Placental tissue is particularly sensitive to the characteristic changes which occurs in venous hypertension. In this regard, changes in the extracellular matrix (ECM), that occur to adapt to this situation, are fundamental to controlling elastogenesis. Therefore, the aim of the present study was to analyze the changes that occur in the mRNA and protein expression level of proteins related to elastogenesis in the placental villi of women diagnosed with CVD, in the third trimester of pregnancy. An observational, analytical and prospective cohort study was conducted, in which the placenta from 62 women with CVD were compared with that in placenta from 52 women without a diagnosis of CVD. Gene and protein expression levels were analyzed using reverse transcription-quantitative PCR and immunohistochemistry, respectively. The results showed a significant decrease in the gene and protein expression level of EGFL7 in the placental villi of women with CVD. By contrast, significant increases in the gene and protein expression level of ECM-related proteins, such as tropoelastin, fibulin 4, fibrillin 1 and members of the lysyl oxidase family (LOX and LOXL-1) were also found in the placental villi of women with CVD. To the best of our knowledge, the results from the present study showed for the first time that CVD during pregnancy was associated with changes in the mRNA and protein expres- sion level in essential components of the EGFL7-modulated elastogenesis process in placental villi.

Diabetes mellitus causes severe impairment in the cutaneous wound healing process, which has led to extensive research striving to establish new treatments. In this work, we describe the effects of chitosan hydrogels functionalized with either unfractionated heparin or bemiparin (a low molecular weight heparin, LMWH) as topical treatments in an experimental diabetic wound healing model. Although wound morphometry showed similar values at the end of the study, microscopic analyses revealed impaired healing in diabetic animals in terms of inflammation and tissue formation. However, both types of loaded hydrogels accelerated inflammation resolution and improved the epithelialization process, while showing a neodermal thickness similar to that of nondiabetic animals. Immunohistochemistry analyses revealed an intermediate response in macrophage evolution between diabetic and nondiabetic controls in the treated groups, as well as enhanced collagenization and myofibroblast progression patterns. However, these changes were not accompanied by differences among groups in collagen I, III and TGF-β1 gene expression. Functionalized hydrogels improved diabetes-associated impaired wound healing, thus promoting the progression of the process and inducing the formation of high-quality cicatricial tissue. Although the beneficial healing effect observed after topical treatment with chitosan hydrogels loaded with bemiparin or unfractionated heparin was similar, the chitosan hydrogel loaded with bemiparin is the preferred choice as it exhibited high-quality tissue in the neoformed dermal tissue., This research did not receive any other specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This study was supported by Community of Madrid, Spain (B2017/BMD-3804 MITIC-CM) and cofinanced by the European Development Regional Fund “A way to achieve Europe’’ (ERDF). AC was a recipient of a FPIUAH gran

Simple Summary Mitochondrial microRNAs (mitomiRs) are an emerging field of study in a wide range of tumours including breast cancer. By targeting mitochondrial, or non-mitochondrial products, mitomiRs are able to regulate the functions of this organelle, thus controlling multiple carcinogenic processes. The knowledge of this system may provide a novel approach for targeted therapies, as potential biomarkers or helping in the diagnosis of such a complex malignancy. Abstract Breast cancer is the most prevalent and incident female neoplasm worldwide. Although survival rates have considerably improved, it is still the leading cause of cancer-related mortality in women. MicroRNAs are small non-coding RNA molecules that regulate the posttranscriptional expression of a wide variety of genes. Although it is usually located in the cytoplasm, several studies have detected a regulatory role of microRNAs in other cell compartments such as the nucleus or mitochondrion, known as “mitomiRs”. MitomiRs are essential modulators of mitochondrion tasks and their abnormal expression has been linked to the aetiology of several human diseases related to mitochondrial dysfunction, including breast cancer. This review aims to examine basic knowledge of the role of mitomiRs in breast cancer and discusses their prospects as biomarkers or therapeutic targets.

Background: Chronic venous disease (CVD) is a prevalent lower limb venous pathology that especially affects women, who also show an increased risk of this disease during pregnancy. Studies have shown significant structural changes in the placentas of women with CVD and several markers of tissue damage have been also described. Patients and Methods: To try to understand the different placental pathologies, research efforts have focused on examining metabolomic profiles as indicators of the repercussions of these vascular disorders. This study examines changes produced in the metabolomic profiles of chorionic villi in the placentas of women with CVD. In a study population of 12 pregnant women, 6 with and 6 without CVD, we compared through mass spectroscopy coupled to ultra-high performance liquid chromatography (UHPLC-MS), 240 metabolites in chorionic villus samples. Results: This study is the first to detect in the placental villi of pregnant women with CVD, modifications in lysophosphatidylcholines and amino acids along with diminished levels of other lipids such as triglycerides, sphingomyelins, and non-esterified omega 9 fatty acids, suggesting a role of these abnormalities in the pathogenesis of CVD. Conclusions: Our findings are a starting point for future studies designed to examine the impacts of CVD on maternal and fetal well-being., This study (FIS-PI18/00912) was supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013-2016) and cofinanced by the European Development Regional Fund “A way to achieve Europe” (ERDF) and B2017/BMD-3804 MITIC-CM.

IntroductionAndrogenetic alopecia (AGA) or male pattern baldness is a polygenic disease with a high prevalence in the Caucasian population, with psychosocial implications. However, the molecular mechanisms involved are unknown. The aim of this study was to assess the possible changes in protein expression of cytokeratin 15 (CK15), tropoelastin (TE) and cellular senescence markers (p15/p16) in AGA patients.Material and methodsAn observational, analytical and prospective cohort study was performed in 57 men with AGA (42.31 ±3.01 years). Two tissue biopsies were taken: the control area (C) and the alopecia area (A). Cell viability was assessed using scalp explants from the patients, maintaining explants long term (90 days). Protein expression analysis was performed by immunohistochemistry by detecting antigen-antibody reactions (avidin-biotin complex).Resultshe results showed a significantly higher percentage of dead cells in area A (17.00 ±1.09% C vs. 28.50 ±1.41% A, *p < 0.05). The area affected by alopecia showed significantly lower CK15 and TE protein expression in hair follicles, sebaceous glands and epidermis (*p < 0.05). Expression of the senescence marker p15/p16 was significantly higher in hair follicles, hair bulbs and the epidermis (*p < 0.05).ConclusionsThe results suggest that patients with AGA suffer tissue damage that affects different components of hair follicle stem cells as well as the extracellular matrix itself.

Pregnancy is a period in a woman&rsquo, s life associated with an increased risk of developing lower extremity chronic venous disease (CVD). Pregnancy-associated CVD is associated with changes in placental villi. We investigated angiogenesis and lymphangiogenesis in the placental villi of women with CVD during pregnancy compared with healthy controls with no history of CVD (HC). An observational, analytical, and prospective cohort study was conducted on 114 women in their third trimester of pregnancy (32 weeks). Sixty-two participants were clinically diagnosed with CVD. In parallel, 52 controls with no history of CVD (HC) were studied. Gene and protein expression of CD31, podoplanin (D2-40), Flt-1, and placental growth factor (PIGF) was analysed by real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry. CD31 and D2-40 gene expression was significantly greater in the placental villi of women with CVD, as were the numbers of vessels positive for CD31 and D2-40. Significantly higher gene and protein expression of Flt-1 and PIGF was observed in the placental villi of women with CVD. Histological analysis showed more placental villi with periodic acid of Schiff (PAS)-positive material in women with CVD. Our results show a connection between pregnancy-associated CVD and leading to higher proangiogenic and lymphangiogenic activity in placental villi.

Chronic venous disease (CVeD) is defined as a set of disorders affecting the venous system mainly manifested in the form of varicose veins. CVeD is characterized by a sustained venous hypertension, leading to a plethora of functional and structural changes in the vein that may cause valve incompetence and pathologic reflux. In turn, venous reflux aggravates the venous hypertension and enhances the progression of CVeD into the most advanced stages. Previous studies have proposed that there are several alterations in the venous wall preceding the valve dysfunction and venous reflux. Besides, it has also been identified that young patients with CVeD present premature aging and changes in the venous wall composition that may be related to the presence of venous reflux. In this context, the aim of the present study is to examine the possible pathophysiological role of elastic fibers and their precursors in the venous wall of patients with reflux in comparison to those without reflux, considering the variable age in both groups (

Polymer-based composites are a group of biomaterials that exert synergic and combined activity. There are multiple reported uses of these composites in multiple biomedical areas, such as drug carriers, in wound dressings, and, more prominently, in tissue engineering and regenerative medicine. Bone grafting is a promising field in the use of polymeric composites, as this is the second most frequently transplanted organ in the United States. Advances in novel biomaterials, such as polymeric composites, will undoubtedly be of great aid in bone tissue engineering and regeneration. In this paper, a general view of bone structure and polymeric composites will be given, discussing the potential role of these components in bone tissue. Moreover, the most relevant jawbone and maxillofacial applications of polymeric composites will be revised in this article, collecting the main knowledge about this topic and emphasizing the need of further clinical studies in humans.

Chronic venous disease (CVeD) has a remarkable prevalence, with an estimated annual incidence of 2%. It has been demonstrated how the loss of homeostatic mechanisms in the vein wall can take part in the physiopathology of CVeD. In this regard, it has been described how different axis, such as IGF-1/PAPP-A/STC-2 axis, may play an essential role in tissue homeostasis. The aim of this research is to study both genetic and protein expressions of the IGF-1/PAPP-A/STC-2 axis in CVeD patients. It is a cross-sectional study in which genetic (RT-qPCR) and protein (immunohistochemistry) expression analysis techniques were accomplished in saphenous veins from CVeD patients ( n = 35 ) in comparison to individuals without vascular pathology (HV). Results show a significant increase in both genetic and protein expressions of PAPP-A and IGF-1, and a decrement STC-2 expression at the same time in CVeD patients. Our study is a pioneer for demonstrating that the expression of the different components of the IGF-1/PAPP-A/STC-2 axis is altered in CVeD patients. This fact can be a part of the loss of homeostatic mechanisms of the venous tissue. Further research should be destined to deepen into alterations of this axis, as well as to evaluate the usage of these components as therapeutic targets for CVeD.

Breast cancer is the cancer with the highest prevalence in women and is the number-one cause of cancer mortality worldwide. Cell transduction is a fundamental process in the development and progression of cancer. Modifications in various cell signalling pathways promote tumour cell proliferation, progression, and survival. The PI3K/Akt/mTOR pathway is an example of that, and it is involved in growth, proliferation, survival, motility, metabolism, and immune response regulation. Activation of this pathway is one of the main causes of cancer cell resistance to antitumour therapies. This makes PI3K/Akt/mTOR signalling a crucial object of study for understanding the development and progression of this disease. Thus, this pathway may have a role as a potential therapeutic target, as well as prognostic and diagnostic value, in patients with breast cancer. Despite the existence of selective PI3K/Akt/mTOR pathway inhibitors and current clinical trials, the cellular mechanisms are not yet known. The present review aims to understand the current state of this important disease and the paths that must be forged., This work was supported by grants from the B2017/BMD-3804 MITIC-CM (Community of Madrid, Spain), cofinanced by the European Development Regional Fund “A Way to Achieve Europe” (ERDF).

Pregnancy is a period in a woman’s life in which changes can occur that affect different physiological processes. Common conditions during this period include vascular changes, such as lower extremity venous insufficiency (VI). This is an observational, analytical, and prospective cohort study in which 114 pregnant women were analyzed, of which 62 were clinically diagnosed with VI. In parallel, 52 control patients without VI (HC) were studied. The aim of this study was to observe changes in angiogenesis and inflammation markers as well as the presence of calcium deposits. The expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and pigment epithelium-derived factor (PEDF) was analyzed by immunohistochemistry and RT-qPCR. The presence of calcium deposits was revealed using the von Kossa method. In the placentas of mothers with VI, gene expression of VEGF (34.575 [32.380–36.720] VI vs 32.965 [30.580–36.320] HC) and PEDF (25.417 [24.459–27.675] VI vs 24.400 [23.102–30.223] HC) significantly increased, as was protein expression in the placental villi. An increase in calcium deposits was observed in the placentas of women with VI (72.58% VI/53.84% HC). This study revealed the existence of cellular damage in the placental villi of mothers with VI with tissue implications such as increased calcification.

Castleman's disease is an uncommon lymphoproliferative disorder characterized by lymph node enlargement, hyperplasia of lymphoid follicles surrounded by mature lymphocytes, and capillary proliferation with endothelial hyperplasia. Although intracranial location is very uncommon, it should be considered in the differential diagnosis of meningeal tumors. We describe a new case appearing as two solid extraaxial masses simulating meningiomas. This multifocal meningeal involvement can be considered as an exceptional form of presentation of intracranial Castleman's disease.

A correlation between apoptosis and proliferation in astrocytomas and oligodendrogliomas, but not in glioblastomas, has been previously reported. An index for apoptosis and proliferation was established for each tumor in a series of 20 brain metastases, and its correlation was studied using the Spearman rank correlation test. Apoptosis index (AI) ranged between 1 and 78% (mean SD: 11.48+/-16.4). Proliferation index (PI) ranged between 2.4 and 21% (mean+/-SD: 8.23+/-4.8). When the relationship between AI and PI was studied, a clear correlation was found (r: 0.8965, 95% CI: 0.74-0.95; P < 0.0001). Therefore, it is concluded that a clear correlation exists between proliferation and apoptosis in secondary tumors of the brain.

Cell apoptosis in solid tumours has been related to immunological attack by NK-cells. The purpose of the present study is to verify in the tissue of brain metastases a possible relationship among the degree of NK-cell infiltration and the number of apoptotic tumour cells.Twenty brain metastases whose tumour cells expressed CD95 (Fas/APO1) have been studied. NK-cells were identified by using the monoclonal antibody to CD57, and apoptotic tumour cells by means of the immunostain with the anti-ssDNA monoclonal antibody F7-26. The Spearman rank correlation test was used to study the relationship between the degree of CD57-NK-cell infiltration and the apoptosis labelling-index.Positivity to F7-26 was present in all tumour samples, but the number of immunostained cells showed a wide variability, with a mean apoptosis labelling-index of 11.48%. All the studied tumours showed CD57 immunostained cells, with a number that ranged between 4 and 20 per microscopical field at 200x (mean+/-standard deviation: 8.4+/-3.7). Statistical studies showed that there was no correlation between the number of CD57 immunostained NK-cells and the apoptosis labelling-index (p0.05).These findings suggest that in brain metastases, apoptosis related to immune response is mainly mediated by activated tumour-infiltrating mononuclear cells other than CD57(+) NK-cells.

Cell proliferation and cell death are opposing processes in tumour growth, with tumour progression reflecting the balance between proliferating and apoptotic cells. The purpose of the present study is to verify the hypothesis that an imbalance between apoptosis and proliferation can predict survival in patients with primary glioblastoma. After the immunohistochemical study of Apostain and MIB-1 expression, the index of apoptosis (AI), the index of proliferation (PI), and the ratio AI/PI was recorded for each tumour specimen, in a series of 32 primary glioblastomas. Studies of correlation between AI and PI, between AI and survival, between PI and survival, and between the ratio AI/PI and survival, were performed using the Spearman rank correlation test. Furthermore, a comparative study of survival was performed for subgroups of patients with ratio AI/PI greater or lesser than 1, using the log rank test. In the present series, values of AI and PI showed a wide distribution, with a mean±SD of 8.16±7.2, and of 12.69±21.1, respectively. The values for the ratio AI/PI ranged between 0.01 and 6.03 (mean±SD: 1.44±1.60). Statistical study failed to obtain correlation between AI and PI. Survival of patients not correlated with AI neither with PI. The ratio between AI and PI did not correlate with survival either. Nevertheless, when survival for the subgroups of patients showing a ratio AI/PI greater or lesser than 1 was compared, a significant difference was found (p: 0.02). Survival ranged between 50 and 81 weeks (mean of 58.5±11.05 weeks) for the 12 cases showing a ratio AI/PI greater than 1, and it ranged between 8 and 85 weeks (mean: 38.20±25.37 weeks) for the 20 cases showing a ratio AI/PI lesser than 1. Our present results suggest that a clear imbalance between cell proliferation and apoptosis can predict outcome in patients operated on for a primary glioblastoma.

Natural killer (NK) cells have been implied in the resistance against certain tumors and virally-infected cells. The prognostic significance of tumor infiltrating NK cells in primary squamous cell lung carcinoma (SqCLC) has not been fully studied. Fifty patients with primary SqCLC were evaluated for the presence of tumor infiltrating natural killer cells subset CD57 (TINK) after surgery. None of them received adjuvant therapy. Immunohistochemical studies of surgery pieces were performed by using the monoclonal antibody CD57. The number of TINK cells was counted by using a MICRON image analyzer. The total area studied for each tumor was of 1 cm 2 . In this area, 50 intratumoral fields of 0.173 mm 2 were selected. The reference value used was the median (five TINK cells/field) of all tumors analyzed. After a minimun follow-up of 2 years the Kaplan–Meier method was used to obtain survival curves. Multivariate analysis were performed by using the Cox regression model. The survival was significantly better in patients with more than five TINK cells/field (Logrank P =0.0317). According to TNM classification, in those patients screened as stage IB (37 patients) the differences in survival were significantly higher (Logrank P =0.0016). In the multivariate analysis including TNM (surgical–pathologic stage), age, and endoscopy localization, the risk of death in patients with less than five TINK cells/field was 2.50 fold higher (CI 95%; range 1.07–5.85) than in those patients with more than five TINK cells/field. These results show that TINK cells appear to be a prognostic factor in the survival of patients with SqCLC. The possible antitumoral role of these cells in SqCLC is discussed.

The aim of this study was to identify the candidates for natural killer (NK) testing and to define the best methodology. For this purpose a prospective study was performed on 73 women with repeated implantation failure (RIF). RIF was considered to exist in patients not achieving clinical pregnancy after three transfers with at least one good-quality embryo. Idiopathic RIF was considered to exist in patients in whom thrombophilia, hysteroscopy and endometrial culture were normal, and no chromosomal factor was suspected. Thirty-two of the 73 patients were considered to have idiopathic RIF, and 17 fertile women with children were taken as controls. Immunohistochemical staining for endometrial CD56+ and blood CD56+ or CD16+ NK cells measured using flow cytometry were compared during the mid-luteal phase in both patients and controls. Seventeen out of the 32 patients with idiopathic RIF and only one of the controls had >250 CD56 cells per high power field 400× in endometrial biopsy (p

OBJECTIVE AND IMPORTANCE: Intracranial fibromatous tumors are very rare lesions, with few reported cases. CLINICAL PRESENTATION: We report the case of a 34-year-old male patient who experienced seizures resulting from a cystic lesion in the left occipital region, which remained unchanged for 11 years. After the seizures increased in number, magnetic resonance imaging revealed a large cyst with a tumor nodule. INTERVENTION: A left occipital craniotomy was performed, and the tumor was removed. Pathological studies, including immunohistochemical and ultrastructural analyses, indicated that this neoplasm was composed of fibrous and angiomatous components, and a diagnosis of cerebral angiofibroma was established. CONCLUSION: Cerebral and meningeal fibromas are rare neoplasms that differ from solitary fibrous tumors and fibrous meningiomas. When a number of prominent blood vessels are present in a cerebral or meningeal fibroma, a diagnosis of angiofibroma can be considered. It is possible that some nodular brain tumors that were previously described as meningio-angiomatosis could be reclassified as cerebral or meningeal angiofibromas.

The aim of this study is to investigate the usefulness of a vascular endothelial surface score (VESS) and MIB-1 labeling index (MIB-1 LI), in a defined series of glioblastomas, as biological markers with prognostic significance of survival. Tumor tissue and survival were studied in a series of 38 patients with glioblastoma, previously treated by surgical resection and radiotherapy. For each tumor, immunohistochemical and morphornetric studies were performed in order to study MIB-1 LI, and VESS, expressed as the CD-34 immunostained endothelial surface per 1000 tumor cells. The survival for the entire patient population of the series was 48.1 ± 14.1 weeks, and the mean VESS for the tumors of the series ranged from 16.7 to 107 µm2 per 1000 tumor cells (mean: 38.7 ± 18.2). Factors such as age or MIB-1 LI were not significatively associated with survival, but the median survival for the 18 patients with a VESS less than 35 was 50.7 ± 3.7 weeks, versus 45.9 ± 2.8 weeks for the 20 patients showing a VESS higher than 36 (p < 0.05). Our present results suggest that tumor VESS, expressed as the CD-34 immunostained endothelial surface per each 1000 tumor cells, may have usefulness, as angiogenic-related factor influencing survival, in patients with glioblastoma.

Resumen En la presente revision se muestra la experiencia de los autores en el estudio de los patrones de angiogenesis en oligodendrogliomas. Marcando inmunohistoquimicamente el endotelio vascular (CD-34) se aprecia que los oligodendrogliomas malignos muestran un tipico patron glomeruloide de los capilares intratumorales, que contrasta con el aspecto lineal de los capilares correspondientes a los oligodendrogliomas de bajo grado. Cuando se realizan estudios cuantitativos se observa que, al contrario de observaciones descritas en astrocitomas, en oligodendrogliomas de bajo grado (al menos cuado se cumplen las condiciones de haber presentado un indice de Ki-67 inferior a 1% Y haber sido tratados con cirugia y radioterapia) el simple analisis de la densidad vascular no parece constituir un factor pronostico significativo. Sin embargo, si se obtiene significacion pronostica cuando se analiza morfometricamente el area endotelial en relacion al numero de celulas. Pacientes con tumores que presentaron un indice de superficie vascular (ISV) superior a 15 μm 2 tuvieron una supervivencia a 5 y 10 anos del 50 y 0% respectivamente, frente a una supervivencia del 100 y 71% para pacientes cuyos tumores mostraron un ISV inferior a 15 μm 2 .

The presence of vascular endothelial growth/permeability factor (VEG/PF) has been studied in histological specimens from a series of 16 cerebellar hemangioblastomas. In this series, the tumors were classified as presenting a macroscopic solid pattern (4 cases), a mainly solid pattern with macroscopic cysts (4 cases) or a mainly cystic pattern (8 cases). Solid tumors showed a low degree (75% of cases) or moderate degree (25% of cases) of VEG/PF positivity. The mainly solid tumors containing macroscopic cysts showed a moderate degree (50% of cases) or high degree (50% of cases) of VEG/PF positivity. Nevertheless, mainly cystic hemangioblastomas showed a high degree (87.5% of cases) or moderate degree (12.5% of cases) of VEG/PF positivity. These findings suggest that the predominance of a cystic or solid macroscopic appearance of cerebellar hemangioblastomas may be influenced by the degree of VEG/PF expression within the tumor tissue.

Cyclosporine A induces apoptosis in murine tubular epithelial cells: Role of caspases. Background The pathogenesis of cyclosporine A (CsA) nephrotoxicity has not been completely elucidated. Methods The ability of CsA to induce apoptosis in cultured murine tubular epithelial cells and its regulation by the cell microenvironment and inhibitors of caspases were studied. Results This study found that CsA induces apoptotic death in murine proximal tubular epithelial MCT cells in a dose- (0.1 to 15 μg/ml) and time-dependent (24 to 72 hr) manner. Death caused by CsA is additive to apoptosis induced by deprivation of the survival factors present in serum. Primary cultures of murine tubular epithelial cells are also sensitive to CsA-induced apoptosis. Peptide inhibitors of caspases such as zVAD-fmk (which inhibits caspases 8 and 9) and DEVD-CHO (which inhibits caspase 3 and related caspases) prevented CsA-induced apoptosis in MCT cells, although zVAD-fmk was effective at lower concentrations. Conclusion These data suggest that tubular cell apoptosis mediated by caspases may play a role in CsA nephrotoxicity and that the microenvironment modulates resistance to CsA lethality as low local levels of survival factors may potentiate nephrotoxicity. Caspases my be new therapeutic targets in the management of nephrotoxic injury.

Resumen Se ha realizado un estudio experimental sobre un modelo de tumor neuroectodermico indiferenciado, con el proposito de conocer el posible efecto antitumoral de un derivado de la tetraciclina (minociclina) con capacidad para inducir una inhibicion de la angiogenesis tumoral. La administracion intratumoral de minociclina sobre el tumor experimental IL-7, durante 4 semanas, no modifico el crecimiento del tumor ni su patron de angiogenesis. Estos resultados sugieren la escasa utilidfld de lineas de investigacion que traten de controlar el crecimiento de neoplasias indiferenciadas del Sistema Nervioso basandose en una supuesta inhibicion de la angiogenesis tumoral inducida por derivados de la tetraciclina.

Intratumoural administration of gangliosides (GSD) into a murine primitive neuro-ectodermal tumour, growing in the epicranial subcutaneous tissue of syngenic rats, results in a decrease in the tumour growth rate and causes a more differentiated phenotype of tumour cell, with immunohistochemical expression of neuronal markers. These findings suggest that the potential usefulness of intralesional administration of GSD for the control of tumours of primitive neuro-epithelial character could be considered.

Resumen Se ha realizado un estudio experimental sobre el tumor IL-7, implantado subcutaneamente en ratas Wistar, al objeto de verificar si la administracion sistemica o intralesional de dexametasona puede ejercer un efecto antitumoral. Los resultados obtenidos muestran que, tras cuatro semanas de tratamiento, la administracion de este farmaco, ya sea por via sistemica o mediante inyeccion directa intratumoral, no modifica significativamente el volumen del tumor ni el indice de proliferacion celular. Teniendo en cuenta el caracter neuroectodermico primitivo del tumor IL-7, los presentes resultados sugieren la ineficacia de la dexametasona, como agente citolitico, sobre neoplasias cerebrales humanas que muestren caracteristicas histologicas de tumor neuroectodermico primitivo.

Resumen Los llamados «Tumores neuroepiteliales disembrioplasicos » (TND) fueron individualizados en 1988 por Daumas-Duport y cols. Clinicamente se manifiestan por una historia de larga evolucion consistente en crisis epilepticas rebeldes al tratamiento medico. Anatomopatologicamente sus celulas predominantes son de pequeno tamano, con aspecto similar, desde el punto de vista de la microscopia optica, al de las celulas de oligodendroglia, y se asocian a alteraciones neuronales, con desorganizacion de la corteza cerebral. En la presente publicacion se aportan 2 nuevos casos de TND y se revisan los aspectos anatomoclinicos de esta entidad. Nuestros hallazgos confirman observaciones previas en el sentido de que estas neoplasias son biologicamente benignas y constituyen basicamente lesiones epileptogenicas susceptibles de ser tratadas quirurgicamente con magnificos resultados. Por otra parte, el estudio anatomopatologico realizado en nuestros casos demuestra la naturaleza neuronal de estos tumores, lo que unido a observaciones recogidas en la literatura, nos lleva a sugerir que los llamados «tumores neuroepiteliales disembrioplasicos» deberian ser reclasificados como «neurocitomas disembrioplasicos».

A series of 122 experimental brain tumours, induced in the Wistar rat by means of prenatal exposition to ethyl-nitrosourea, were studied with histological, immunohistochemical and ultrastructural techniques. Although with conventional histological techniques, most of the induced tumours showed morphological features suggesting their classification as malignant schwannomas or oligodendroglioma-like neoplasms, their study by means of immunohistochemistry and electron microscopy suggested that they are, in fact, primitive neuroectodermal tumours, with a tendency toward neuronal differentiation. This finding obliges us to re-appraise the ethyl-nitrosourea model of neurocarcinogenesis and to consider its possible usefulness for the experimental study of therapeutic approaches with potential applications in human neuro-ectodermal neoplasms.

Resumen Se ha realizado un estudio experimental mediante protocolos de inmunoterapia adoptiva sobre un tumor neuroectodermico primitivo de origen murino con ca­ pacidad de diferenciacion neuroblastica (tumor IL-7). Los resultados obtenidos muestran que la administra­ cion intratumoral de interferon-alfa 2b o de interIeu­ quina-2, a lo largo de cuatro semanas, sobre el tumor 11-7 implantado en el tejido subcutaneo epicraneal, no modifica el ritmo de crecimiento tumoral. Sin embar­ go, la administracion intratumoral de celulas NK, ce­ lulas LAK y celulas TIL, consigue retrasar significati­ vamente el ritmo de crecimiento tumoral. Estos hallaz­ gos confirman resultados previos obtenidos en el caso de pacientes con gliomas malignos y plantean la conve­ niencia de nuevos estudios de inmunoterapia adoptiva con linfocitos activados en pacientes con tumores neu­ roectodermicos indiferenciados. PALABRAS CLAVE: Tumores neuroectodermicos pri­ mitivos, Inmunoterapia, Celulas NK, Celulas LAK, Celu­ las TIL, Interferon, Interleuquina-2. Neuro-oncologia ex­ perimental. Summary

Resumen Presentamos un caso de tumor neuroectodermico primitivo originado en el nervio ciatico, en un paciente con un cuadro clinico de ciatalgia intensa desencadenada siempre al sentarse y un abultamiento notable en la region glutea derecha. En la intervencion quirurgica, se identifico en el tronco del nervio ciatico, en el trayecto situado ligeramente por encima del pliegue gluteo, una tumoracion fusiforme de 8 × 12 cm, que englobaba el nervio. Histologicamente, el tumor estaba constituido por celulas neoplasicas de nucleos redondeados, relativamente uniformes y escaso citoplasma. Junto a numerosas imagenes de mitosis, estaban significativamente representadas estructuras rosetoides, en las que las celulas neoplasicas se disponian en corona con centros fibrilares (Rosetas de Homer-Wright). Con M. E. se observaron celulas pobremente diferenciadas, de pequeno tamano, con escasas prolongaciones citoplasmaticas, raros microtubulos y aislados granulos electrodensos. Con tecnicas de inmunohistoquimia, se detecto inmunoreactividad debil para NSE y moderada y zonal para sinaptofisina. En conclusion, pensamos que se trata de una neoplasia maligna de nervio periferico, rara, originada a partir de celulas neuroepiteliales primitivas, con caracteristicas microscopicas, ultraestructurales e inmunohistoquimicas similares a las de los Tumores Neuroectodermicos Primitivos del Sistema Nervioso Central.

Delayed transplantation of foetal cerebral tissue into injured spinal cord of adult rats was performed for the purpose of evaluating the usefulness of the procedure for reconstructing the spinal cord and providing motor recovery. Transplanted tissue showed a survival rate greater than 80% and integration with the host tissue. Nerve fibers of the host surrounded the transplanted tissue, penetrating it. Foetal cerebral neurons matured into recipient spinal cord, but they were not organized in layers. The experience obtained suggests that delayed transplantation of foetal cerebral tissue into contused spinal cord is useful in morphological spinal cord reconstruction. Nevertheless, at least during the first two months after transplantation, clinical assessment of motor recovery showed no differences between transplanted and nontransplanted rats.

Resumen En el presente estudio se revisan los conocimientos actuales acerca del valor de las tecnicas inmunohistoquimicas para el diagnostico de los tumores cerebrales. La especificidad de los diferentes marcadores y su utilidad real son discutidas y contrastadas en base a la experiencia obtenida por los autores tras el estudio inmunohistoquimico de 228 tumores cerebrales.

Summary Intraparenchymatous cerebral cysts covered by choroid epithelium are extremely uncommon malformative lesions. We present three cases of extraventricular choroid cysts which became symptomatic in patients at 38, 60 and 65 years of age. The identification, at least in two of these cases, of venous structures fIoating inside the cystic cavity suggests a mechanism of secretion and reabsortion of CSF, the alteration of which could lead to the growth of the cyst. At present, immunohistochemical study of epithelium that covers the socalled neuroepithelial cysts of the brain can achieve a better knowledge of these malformative lesions and to help in the selection of the best therapeutic approach for each case.

Resumen Se muestra la experiencia obtenida en la induccion de tumores experimentales del Sistema Nervioso en la rata Wistar, tras la exposicion a etil-nitrosourea (ENU) durante el periodo fetal. En las condiciones experimentales utilizadas (inyeccion IP de 50 mg/kg de ENU en el dia 17 de gestacion), se obtuvieron schwanomas, generalmente del trigemino y/o ganglio de Gasser, con una latencia que oscilo entre 4 y 7 meses, y tumores intracerebrales con aspecto morfologico de oligodendrogliomas, tras una latencia que oscilo entre 7 y 10 meses tras la exposicion al carcinogeno. El estudio inmunohistoquimico de ambos tipos de tumores mostro una clara positividad a la sinaptofisina, y en menor grado a la vimentina, lo que sugiere que, independientemente de su aspecto histologico, las neoplasias experimentales inducidas por ENU deben ser consideradas como tumores neuroectodermicos primitivos.

Three basic types of cells are distinguished in the rat vomeronasal epithelium at birth: bipolar neurons, supporting cells, and basal cells. Neurons at this time include both immature and differentiated cells. By the end of the first postnatal week, all neurons show morphological signs of maturity in their cytoplasm, including abundant granular and smooth endoplasmic reticulum, neurotubules, dense lamellar bodies, apical centrioles, and tufts of microvilli. During the third week microvilli are more frequently encountered and appear to be longer and more branched. Supporting cells appear well-developed by the second day after birth. During the first ten days of life, supporting cells lose their centrioles and all of the complex associated with ciliary generation in the apical zone. Basal cells appear to be more numerous in newborns than in older animals. Protrusions projecting into the lumen are frequently observed in the epithelium of newborn animals, both on the dendrites of neurons and on supporting cells. After the third week, such protrusions are only observed in the transitional zone between the sensory and the non-sensory epithelia of the vomeronasal tubes. In this transitional zone, a fourth cell type showing apical protrusions with microvilli differentiates. Cytoplasm in this type resembles that of neighboring ciliated cells but has no cilia or centrioles. These transitional cells are considered to be cells in an intermediate state of differentiation, between that of the differentiated neurons and supporting cells of the sensory epithelium and that of the predominate ciliated cells of the non-sensory epithelium. The results suggest that by the end of the third week the vomeronasal epithelium is morphologically mature.

Seven glioblastomas were studied between 1 and 6 months after intratumoral injection of autologous lymphocytes and human lymphoblastoid interferon. Morphological study showed a great number of lymphocytes within the tumor tissue, and interactions between lymphocytes and glioblastoma cells, suggesting a killing phenomenon. These data support the potential usefulness of adoptive immunotherapy in patients with glioblastoma by means of intratumoral administration of activated lymphoid cells.

Resumen En los oligodendrogliomas la microscopia electronica muestra celulas tumorales con caracteristicas morfologicas propias de los oligodendrocitos. Un detalle caracteristico es la observacion de que las prolongaciones de las celulas del tumor muestran tendencia a formar laminillas concentricas que se interpretan como un intento de formacion de vainas de mielina.

We describe a 34-year-old man who presented with headaches for about 3 months. Magnetic Resonance Imaging (MRI) revealed a large cystic tumor, involving the right frontoparietal lobe region. Pathological study revealed a papillary glioneuronal tumor (PGNT) with mitotic activity and a Ki-67 labeling index of approximately 15%. Five years after radical surgery and radiotherapy, the patient is symptom-free, without tumor recurrence or residual tumor. This case supports the existence of an atypical variant of PGNT, with mitotic activity and high proliferative index, and suggests that in these tumors, histological findings of malignity not necessarily indicate a short-term unfavorable behavior.