Transdiaphragmatic intercostal hernia induced by sternutation: A case report.

INTRODUCTION AND IMPORTANCE: Sternutation is, by definition, a situation that increases abdominal pressure. However, it has not been clearly linked to protrusion of abdominal content through weaknesses in the abdominal boundaries. CASE PRESENTATION: Here we present a case report in which the only trigger factor found for an abdominal content protrusion was a sternutation episode. The patient arrived in our institution with the diagnosis of a transdiaphragmatic intercostal hernia, proven in CT-scan. He was, then, submitted to emergent surgery, where through thoracotomy and subcostal laparotomy, hernia content was reduced. The patient had a favorable evolution. CLINICAL DISCUSSION: TDIH is a rare entity, for which there are still no consensus regarding its management. This makes clinical practice more challenging, leaving to the surgeon the therapeutic decision tailored to each patient. CONCLUSION: This entity should be further studied, and consensus reached regarding its management.

Clinical outcomes in patients with diabetes and stress hyperglycemia that developed SARS-CoV-2 infection / Desenlaces clínicos de los pacientes con diabetes e hiperglucemia de estrés que presentaron infección por SARS-CoV-2

Introduction. Diabetes and stress hyperglycemia have been related with poorer clinical outcomes in patients infected by SARS-CoV-2 and at risk for severe disease. Objective. To evaluate clinical outcomes in three groups of patients (with diabetes, without diabetes and with stress hyperglycemia) with SARS-CoV-2 infection. Materials and methods. A retrospective cohort study was conducted in Cali (Colombia). We included patients 18 years old or older with a diagnosis of SARS-CoV-2 infection, managed in the emergency room, hospitalization, or intensive care unit between March 2020 and December 2021. Immunocompromised patients and pregnant women were excluded. Patients were classified into three groups: without diabetes, with diabetes, and with stress hyperglycemia. A comparison between the groups was performed. Results. A total of945 patients were included (59.6% without diabetes, 27% with diabetes, and 13.4% with stress hyperglycemia). Fifty-five-point three percent required intensive care unit management, with a higher need in patients with stress hyperglycemia (89.8%) and diabetes (67.1%), with no difference between these groups (p = 0.249). We identified a higher probability of death in the group with stress hyperglycemia versus the one without diabetes (adjusted OR = 8.12; 95% CI: 5.12-12.88; p < 0.01). Frequency of acute respiratory distress syndrome, need for invasive mechanical ventilation, use of vasopressors and inotropes, need for de novo renal replacement therapy, and mortality was higher in patients with metabolic alterations (diabetes and stress hyperglycemia). Conclusions. Diabetes and stress hyperglycemia were associated with worse clinical outcomes and mortality in patients with COVID-19. These patients should be identified early and considered them high risk at the COVID-19 diagnosis to mitigate adverse outcomes.

Introducción. La diabetes y la hiperglucemia de estrés se han relacionado con peores desenlaces clínicos en pacientes infectados por SARS-CoV-2 y con riesgo de enfermedad grave. Objetivo. Evaluar los resultados clínicos en tres grupos de pacientes (con diabetes, sin diabetes o con hiperglucemia de estrés) con infección por SARS-CoV-2. Materiales y métodos. Se llevó a cabo un estudio retrospectivo de cohorte en Cali (Colombia). Se incluyeron pacientes de 18 años o más, con diagnóstico de infección por SARS-CoV-2 atendidos en urgencias, hospitalización o unidad de cuidados intensivos entre marzo de 2020 y diciembre de 2021. Se excluyeron los pacientes inmunocomprometidos y las mujeres embarazadas. Los pacientes fueron clasificados en tres grupos: sin diabetes, con diabetes y con hiperglucemia de estrés. Se realizó una comparación entre los grupos. Resultados. Se incluyeron 945 pacientes (59,6 % sin diabetes, 27 % con diabetes y 13,4 % con hiperglucemia de estrés). El 55,3 % requirió manejo en la unidad de cuidados intensivos, con mayor necesidad por parte de los pacientes con hiperglucemia de estrés (89,8 %) y diabetes (67,1%), sin diferencia entre estos grupos (p = 0,249). Se observó una mayor probabilidad de muerte en el grupo con hiperglucemia de estrés versus sin diabetes (OR ajustado = 8,12; IC95%: 5,12-12,88; p < 0,01). La frecuencia de síndrome de distrés respiratorio agudo, necesidad de ventilación mecánica invasiva, uso de vasopresores e inotrópicos, necesidad de terapia de reemplazo renal de novo y mortalidad fue mayor en pacientes con alteraciones metabólicas (diabetes e hiperglucemia de estrés). Conclusiones. La diabetes y la hiperglucemia de estrés se asociaron a peores resultados clínicos y mortalidad en pacientes con COVID-19. Estos pacientes deben ser identificados tempranamente y considerados de alto riesgo al momento del diagnóstico de COVID-19 para mitigar los desenlaces adversos.

Absceso hepático en Cali, Colombia / Liver abscess in Cali, Colombia

INTRODUCCIÓN: El absceso hepático (AH) es el tipo mas común de abscesos viscerales. Se estima que el perfil epidemiológico de esta enfermedad ha cambiado con el aumento de la resistencia de los microorganismos y el uso de nuevos medicamentos. OBJETIVO: Describir las características demográficas y clínicas de los pacientes hospitalizados con diagnóstico de AH en un hospital universitario del suroccidente colombiano. MÉTODOS: Se realizó un estudio observacional retrospectivo, en la Fundación Valle del Lili, Cali, Colombia. Se incluyeron pacientes mayores de 18 años con diagnóstico de AH hospitalizados entre 2011-2020. RESULTADOS: Se incluyeron 182 pacientes. La mediana de edad fUe 56 años (rango intercuartílico, 45-67) y 62,1% fueron hombres. El microrganismo mas común fue Klebsiella pneumoniae (17,6%). La mayoría requirió drenaje percutáneo (58,2%). El 58,8% tuvo un absceso único y 54,4% fue manejado en cuidados intensivos. El 7,1% de los pacientes falleció. Al comparar los casos que fueron manejados en cuidados intensivos vs. aquellos que no lo fueron, hubo más hepatomegalia (28,3 vs. 11,0%, p = 0,004), derrame pleural derecho (48,5 vs. 28,1%, p = 0,010), cirugía (42,4 vs. 13,4%, p < 0,001), falla terapéutica (22,2 vs. 7,3%, p = 0,007) y muerte (12,1 vs. 1,2%, p = 0,005) en los atendidos en UCI. CONCLUSIÓN: Las Enterobacterales son la principal causa de AH en nuestra población. La mortalidad ha disminuido, pero la hospitalización en cuidados intensivos sigue siendo alta.

BACKGROUND: Liver abscess (LA) is the most common type of visceral abscess. It is estimated that the epidemiological profile of this disease has changed with the increase in resistance and the use of new drugs. AIM: To describe the demographic and clinical characteristics of hospitalized patients with a diagnosis of LA in a university hospital in the southwestern region of Colombia. METHODS: A. retrospective observational study was conducted at Fundación Valle del Lili, Cali, Colombia. Patients older than 18 years with a diagnosis of LA hospitalized between 2011-2020 were included. RESULTS: A total of 182 patients were included. The median age was 56 years (interquartile range, 45-67) and 62.1% were men. The most common microorganism was Klebsiella pneumoniae (17.6%). The majority required percutaneous drainage (58.2%). A 58.8% had a single abscess and 54.4% were treated in ICU. A 7.1% of the patients died. When comparing cases treated in the ICU vs. those who did not, there was more hepatomegaly (28.3 vs. 11.0%, p = 0.004), right pleural effusion (48.5 vs. 28.1%, p = 0.010), surgery (42.4 vs. 13.4%, p < 0.001), therapeutic failure (22.2 vs. 7.3%, p = 0.007) and death (12.1 vs. 1.2%, p = 0.005) in patients treated in ICU. CONCLUSION: Enterobacterales are the main cause of LA in our population. Mortality has decreased, but intensive care hospitalization remains high.

Hemorrhagic Cerebrovascular Disease: An Unusual Presentation of Hyperhomocysteinemia / Accidente cerebrovascular hemorrágico: una inusual presentación de hiperhomocisteinemia / Acidente vascular cerebral hemorrágico: uma apresentação incomum da hiper-homocisteinemia

Introduction: Stroke is a major cause of morbidity and mortality worldwide, with hemorrhagic stroke being the deadliest form of acute stroke. Therefore, the cause of the event should be determined to direct the associated therapy and take preventive measures. Hyperhomocysteinemia has been described as a rare etiology of stroke. Although hyperhomocysteinemia has been associated with venous thrombotic events, altered endothelial function, and procoagulant states, its clinical role in stroke remains controversial. Case description: We present a case of a 60-year-old male patient with primary autoimmune hypothyroidism who presented with dysarthria, facial paresis, and left upper-limb monoparesis after sexual intercourse. A simple skull computed tomography scan showed hyperintensity in the right basal ganglion, indicating an acute hemorrhagic event. Etiological studies were performed, including ambulatory blood pressure monitoring, cerebral angiography, and transthoracic echocardiogram, which ruled out underlying vascular pathology. During follow-up, vitamin B12 deficiency and hyperhomocysteinemia were detected, without other blood biochemical profile alterations. Supplementation was initiated, and homocysteine levels gradually decreased, without new neurological deficits observed during follow-up. Conclusion: Quantification of homocysteine should be considered in patients with a cerebrovascular disease without apparent cause, as documenting hyperhomocysteinemia and correcting its underlying etiology are essential not only for providing appropriate management but also for preventing future events.

Introducción: el accidente cerebrovascular es una causa importante de morbilidad y mortalidad en todo el mundo, y el accidente cerebrovascular hemorrágico es la forma más mortífera de accidente cerebro- vascular agudo. La determinación de la causa del evento es esencial para dirigir la terapia asociada y poder tomar medidas preventivas. La hiperhomocisteinemia se ha descrito como una etiología poco frecuente de accidente cerebrovascular. Aunque esta se ha asociado con eventos trombóticos venosos, disfunción endotelial alterada y estados procoagulantes, sigue siendo controvertido su papel clínico en el accidente cerebrovascular. Descripción del caso: se presenta el caso de un hombre de 60 años con hipotiroidismo autoinmune primario que presentó disartria, paresia facial y monoparesia del miembro superior izquierdo después de un encuentro sexual. Una simple tomografía computarizada de cráneo mostró hipointensidad en la región del ganglio basal derecho, que indicaba un evento hemorrágico agudo. Se realizaron estudios etiológicos, incluyendo monitorización ambulatoria de la presión arterial, angiografía cerebral y ecocardiograma transtorácico, que descartaron patología vascular subyacente. Durante el seguimiento, se detectó deficiencia de vitamina B12 e hiperhomocisteinemia, sin otras alteraciones en el perfil bioquímico sanguíneo. Se inició la suplementación y los niveles de homocisteína disminuyeron gradualmente, sin observar nuevos déficits neurológicos durante el seguimiento. Conclusión: la cuantificación de homocisteína debe ser considerada en casos de enfermedad cerebrovascular sin causa aparente, dado que documentar la hiperhomocisteinemia y corregir su etiología subyacente es esencial no solo para proporcionar un manejo adecuado, sino también para prevenir eventos futuros.

Introdução: o acidente vascular cerebral (AVC) é uma das principais causas de morbidade e mortalidade em todo o mundo, sendo o AVC hemorrágico a forma mais letal de AVC agudo. A determinação da causa do evento é essencial para direcionar a terapia associada e poder tomar medidas preventivas. A hiperhomocisteinemia tem sido descrita como uma etiologia rara de acidente vascular cerebral. Embora a hiper-homocisteinemia tenha sido associada a eventos trombóticos venosos, disfunção endotelial alterada e estados pró-coagulantes, seu papel clínico no AVC permanece controverso. Descrição do caso: apresentamos o caso de um homem de 60 anos com hipotireoidismo autoimune primário que apresentou disartria, paresia facial e monoparesia do membro superior esquerdo após relação sexual. A tomografia computadorizada de crânio mostrou hipointensidade na região do gânglio da base direito, indicando evento hemorrágico agudo. Foram realizados estudos etiológicos, incluindo monitorização ambulatorial da pressão arterial, angiografia cerebral e ecocardiograma transtorácico, que descartaram patologia vascular subjacente. Durante o acompanhamento, foram detectados deficiência de vitamina B12 e hiper-homocistei- nemia, sem outras alterações no perfil bioquímico sanguíneo. A suplementação foi iniciada e os níveis de homocisteína diminuíram gradualmente, sem novos déficits neurológicos observados durante o acompanhamento. Conclusão: a quantificação da homocisteína deve ser considerada em casos de doença vascular cerebral sem causa aparente, pois documentar a hiper-homocisteinemia e corrigir sua etiologia subjacente é essencial não apenas para fornecer manejo adequado, mas também para prevenir eventos futuros.

Analysis of neutropenia as a predictive factor of the efficacy of trifluridine-tipiracil treatment.

OBJECTIVES: Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN)). MATERIALS AND METHODS: We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study. RESULTS: We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023). CONCLUSION: A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Adrenal Neuroblastoma Producing Catecholamines Diagnosed in Adults: Case Report.

Neuroblastoma is a solid tumor considered almost exclusively pediatric, with more than 95% of patients diagnosed before 10 years of age, with a mostly benign clinical course and with encouraging survival rates in these age ranges. It occurs rarely in adolescents, and the presentation in young adults or older people is even rarer; consequently, a more severe prognosis and higher mortality rates have been documented within this population. This is also due to a great limitation within the treatment since the chemotherapeutic regimens proposed so far are valid for pediatric patients, with low tolerance to it within the adult population. We present the case of a 24-year-old female patient with catecholamine-secreting neuroblastoma who obtained surgical management, with subsequent local tumor recurrence, with subsequent need for onco-specific and symptomatic management.

Depletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease.

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser114 facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Blocking PIN1-MATα1 interaction increased mitochondrial MATα1 levels and protected against alcohol-induced mitochondrial dysfunction and fat accumulation. Normally, MATα1 interacts with mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and fatty acid ß-oxidation. Preserving mitochondrial MATα1 content correlates with higher methylation and expression of mitochondrial proteins. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcohol-associated liver disease.

Treating the N0 neck in early stage oral cancer: a pause for re-assessment?

The incidence of metastases following neck dissection in the apparent lymph node negative neck in oral cancer is between 7% and 33%; early resection of cervical metastases may well increase survival. Modern imaging techniques can reduce the yield of previously undiagnosed metastatic nodes in elective neck dissection (END). An audit of 112 consecutive cases was conducted to determine the proportion of undiagnosed nodal metastases, after END. There were neck metastases in 10 cases (9%), which were mainly (but not all) micrometastic. The 20% likelihood of nodal metastases was only apparent in primary tumours greater than 6 mm thick. The length of inpatient stay was increased from 3.7 to 16.5 days with free vascularised transfer. There were complications including cranial nerve damage. There were two peri-operative deaths. No ipsilateral neck failures occurred, median follow up was 937 days. To reduce unnecessary END, resection can be undertaken as a prior procedure, subsequently only carrying out END on tumours greater than 6 mm, or with unfavourable tumour characteristics.

Metalloproteinases 1 and 3 as Potential Biomarkers in Breast Cancer Development.

Breast cancer continues to be one of the main causes of morbidity and mortality globally and was the leading cause of cancer death in women in Spain in 2020. Early diagnosis is one of the most effective methods to lower the incidence and mortality rates of breast cancer. The human metalloproteinases (MMP) mainly function as proteolytic enzymes degrading the extracellular matrix and plays important roles in most steps of breast tumorigenesis. This retrospective cohort study shows the immunohistochemical expression levels of MMP-1, MMP-2, MMP-3, and MMP-9 in 154 women with breast cancer and 42 women without tumor disease. The samples of breast tissue are assessed using several tissue matrices (TMA). The percentages of staining (≤50%->50%) and intensity levels of staining (weak, moderate, or intense) are considered. The immunohistochemical expression of the MMP-1-intensity (p = 0.043) and MMP-3 percentage (p = 0.018) and intensity, (p = 0.025) present statistically significant associations with the variable group (control-case); therefore, expression in the tumor tissue samples of these MMPs may be related to the development of breast cancer. The relationships between these MMPs and some clinicopathological factors in breast cancer are also evaluated but no correlation is found. These results suggest the use of MMP-1 and MMP-3 as potential biomarkers of breast cancer diagnosis.

Reproducibility of minor salivary gland biopsy reports in Sjögren's syndrome and its correlation with disease biomarkers.

INTRODUCTION/OBJECTIVE: Sjögren's syndrome (SS) is a systemic autoimmune disease that is challenging to diagnose. Although minor salivary gland biopsy (MSGB) is a useful ancillary study, different factors make its interpretation difficult. Also, the significance of distinct histopathological findings is unknown. We aimed to determine the concordance between pathologists and rheumatologists in interpreting the MSGB results, as well as the correlation between MSGB findings, paraclinical features, and SS diagnosis. METHODS: This descriptive retrospective study reviewed medical charts from 998 individuals from a single center where MSGBs had been performed. Rheumatologists interpreted biopsy reports from pathologists, and interobserver variability was calculated. Logistic regression using immunological parameters and histological findings was performed. RESULTS: We included 998 patients with a median age of 55 years (45-64 years); the majority of patients were females (n = 934, 93.6%). Chisholm and Mason's scoring system was the most frequently used scale (55.1%). There was a good correlation between pathologists and rheumatologists for diagnosing SS using MSGB findings (Cohen's kappa 0.91). We observed a strong association between interstitial plasmocytes and SS (OR 24, 95% CI 9.09-64.94, p = 0). CONCLUSION: The MSGB is an essential tool for the diagnosis of SS. Although different factors may negatively affect its reproducibility, histological findings, such as interstitial plasmocytes, may predict the risk of developing SS. Key Points • We provide information based on 998 patients with suspected SS diagnosis. • Chisholm and Mason's scale is the most frequently used compared to Greenspan's and Tarpley's scales. • There is good correlation between pathologists and rheumatologists for the diagnosis of SS using MSGB.

Balance disorders as potential confounders associated with an increased risk of acute cerebrovascular accidents.

PURPOSE: There is a higher risk of stroke after suffering from balance disorders (BDs) such as vertigo or dizziness. The causal relationship remains unclear due to the limited scope of the existing studies and the high prevalence of cardiovascular risk factors (CVRFs) in BD patients. The objective of this study is to clarify the role that BDs seem to have in the development of acute cerebrovascular accidents (ACAs). METHODS: This is an observational prospective study. The CVRFs and demographic factors of a sample of our population were noted. Five clusters of patients were tracked over the course of 2 years to detect and diagnose BDs and ACAs. The causal relationships between the CVRFs, BDs and ACAs were analyzed in a univariate analysis. A logistic regression multivariant analysis was performed on those variables that reached statistical significance. RESULTS: The sample included 7886 participants and 31 ACAs were recorded. CVRFs that reached statistical significance included age ≥ 60, hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, atrial fibrillation and previous ACAs. The relationship between BDs and ACAs always reached statistical significance, regardless of how the BD variable was defined. Five different multivariate analyses were performed, but in none of them did the BD variables significantly reduce the deviance and thus, they were not taken into account when building the final model. CONCLUSION: This study shows that BDs are probably confounders that are closely linked to other CVRFs and they are also useful red flags to identify patients at a higher risk of suffering from ACAs.

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer.

Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial-mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

miRNAs as radio-response biomarkers for breast cancer stem cells.

In breast cancer (BC), the presence of cancer stem cells (CSCs) has been related to relapse, metastasis, and radioresistance. Radiotherapy (RT) is an extended BC treatment, but is not always effective. CSCs have several mechanisms of radioresistance in place, and some miRNAs are involved in the cellular response to ionizing radiation (IR). Here, we studied how IR affects the expression of miRNAs related to stemness in different molecular BC subtypes. Exposition of BC cells to radiation doses of 2, 4, or 6 Gy affected their phenotype, functional characteristics, pluripotency gene expression, and in vivo tumorigenic capacity. This held true for various molecular subtypes of BC cells (classified by ER, PR and HER-2 status), and for BC cells either plated in monolayer, or being in suspension as mammospheres. However, the effect of IR on the expression of eight stemness- and radioresistance-related miRNAs (miR-210, miR-10b, miR-182, miR-142, miR-221, miR-21, miR-93, miR-15b) varied, depending on cell line subpopulation and clinicopathological features of BC patients. Therefore, clinicopathological features and, potentially also, chemotherapy regimen should be both taken into consideration, for determining a potential miRNA signature by liquid biopsy in BC patients treated with RT. Personalized and precision RT dosage regimes could improve the prognosis, treatment, and survival of BC patients.

Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study.

Breast cancer (BC) is the most common tumour in women and one of the most important causes of cancer death worldwide. Radiation therapy (RT) is widely used for BC treatment. Some proteins have been identified as prognostic factors for BC (Ki67, p53, E-cadherin, HER2). In the last years, it has been shown that variations in the expression of MMPs and TIMPs may contribute to the development of BC. The aim of this pilot work was to study the effects of RT on different MMPs (-1, -2, -3, -7, -8, -9, -10, -12 and -13) and TIMPs (-1 to -4), as well as their relationship with other variables related to patient characteristics and tumour biology. A group of 20 BC patients treated with RT were recruited. MMP and TIMP serum levels were analysed by immunoassay before, during and after RT. Our pilot study showed a slight increase in the levels of most MMP and TIMP with RT. However, RT produced a significantly decrease in TIMP-1 and TIMP-3 levels. Significant correlations were found between MMP-3 and TIMP-4 levels, and some of the variables studied related to patient characteristics and tumour biology. Moreover, MMP-9 and TIMP-3 levels could be predictive of RT toxicity. For this reason, MMP-3, MMP-9, TIMP-3 and TIMP-4 could be used as potential prognostic and predictive biomarkers for BC patients treated with RT.

The effect of green fertilizers on the ecological structure of soil invertebrate communities in an andisol of Southwestern Colombia / Efecto de fertilizantes verdes en la estructura ecológica de las comunidades de invertebrados edáficos en un suelo andisol del suroestre de Colombia

Introduction: Chemical fertilizers for agriculture can negatively affect the communities of soil invertebrates that contribute to nutrient cycling, nutrient availability, soil formation and fertility. As an alternative, previous work has suggested that green fertilizers (fresh tissue from plants) are effective to preserve soil fertility, without affecting the ecological properties of invertebrate communities. Objective: This work aimed to evaluate how green fertilizers affect the ecological structure of an invertebrate community in an andisol from Southwestern Colombia. Methods: Fresh leaves from seven plant species locally sown and grown in March 2018 were used as the fertilizers by incorporating and mixing them with the soil in 24 experimental subplots. After 45 days of incorporation, the abundance, richness, biomass and diversity of soil invertebrates were measured in three replicate soil cores per subplot and at three depths. Results: Comparing against a control treatment with no fertilization, the richness and abundance of soil invertebrates were up to 14-fold higher in treatments with Alnus jorullensis and Brassica napus, and up to 5-fold higher in treatments with Vicia sativa, Lupinus mutabilis, Plantago lanceolata and Medicago sativa. Diversity indices showed a shift from high dominance by one or a few invertebrate families in the control treatment, to a high diversity and greater evenness in the A. jorullensis, P. lanceolata and M. sativa treatments. Biomass was negatively correlated with richness and abundance, suggesting a possible ecological trade-off worth to evaluate in further research. Conclusions: In general, our results demonstrate that the application of green fertilizers in this Andean environment can significantly improve the ecological status of soil invertebrate communities. These communities ultimately provide the ecological functions for soil dynamics; thus, agroecology practices should consider them as a valuable alternative to balance production and conservation.

Introducción: Los fertilizantes químicos para la agricultura afectan negativamente a las comunidades de invertebrados, las cuales contribuyen al ciclaje, disponibilidad de los nutrientes y a la formación y fertilidad del suelo. Como alternativa, investigaciones previas han sugerido que los abonos verdes (tejido fresco de plantas) son efectivos para conservar la fertilidad del suelo, posiblemente sin afectar los invertebrados. Objetivo: Evaluar como la aplicación de abonos verdes al suelo afecta cuantitativamente estas propiedades en una comunidad de macrofauna edáfica de un andisol al suroccidente de Colombia. Métodos: El follaje fresco de siete especies de plantas sembradas y cultivadas localmente durante marzo 2018 fue utilizado como abono verde, el cual fue incorporado y mezclado con el suelo superficial en 24 subparcelas experimentales. Después de 45 días de aplicar los abonos, se midió la abundancia, riqueza, biomasa y diversidad de la comunidad de invertebrados. Resultados: En comparación a un tratamiento testigo la riqueza y abundancia de invertebrados fue 14 veces más alta en tratamientos con A. jorullensis y B. napus, y cinco veces más alta en tratamientos con V. sativa, L. mutabilis, P. lanceolata y M. sativa. Los índices de diversidad mostraron un cambio desde una dominancia por una o pocas familias de invertebrados en el testigo, a una alta diversidad y equitatividad en los tratamientos con A. jorullensis, P. lanceolata y M. sativa. La biomasa estuvo correlacionada negativamente con la riqueza y la abundancia, sugiriendo un posible trade-off, en este sentido se sugiere que sea estudiada en futuras investigaciones. Conclusiones: En general, estos resultados demuestran que la aplicación de abonos verdes en estos suelos andinos puede mejorar significativamente la presencia de macroinvertebrados en el suelo.

Radiation and Stemness Phenotype May Influence Individual Breast Cancer Outcomes: The Crucial Role of MMPs and Microenvironment.

Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development.

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease.

Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.

Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

INTRODUCTION: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations. Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND. Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient's life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

Valproic acid modulates radiation-enhanced matrix metalloproteinase activity and invasion of breast cancer cells.

PURPOSE: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition. MATERIAL AND METHODS: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 µM trichostatin-A (TSA)]. RESULTS: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression of mmp-1, mmp-3 and mmp-13 and of their regulators timp-1 and timp-2 relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhanced mmp and timp mRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA. CONCLUSION: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition.

FOXO1 locus and acetylcholinesterase inhibitors in elderly patients with Alzheimer's disease.

OBJECTIVE: Acetylcholinesterase inhibitors (AChEIs) may reduce the oxidative stress in brain of Alzheimer's disease (AD) patients. Forkhead box O1 (FOXO1) protein has been reported as the link between oxidative stress and AD. We evaluated a potential association between FOXO1 gene locus and the response to AChEI treatment in patients with sporadic AD. METHODS: In this prospective study, 109 Caucasian AD patients were treated with standard doses of donepezil, galantamine, or rivastigmine for 6 months. Functional and cognitive status were evaluated at baseline and after treatment. Response to therapy was defined according to the National Institute for Health and Clinical Excellence criteria. Genotype analyses, including the APOE polymorphism, were made in blinded fashion. RESULTS: A significantly higher frequency of FOXO1 rs7981045 G/G genotype was observed in nonresponders compared with responders (17.14% versus 2.70%, P=0.010). Age, sex, and APOE-adjusted logistic regression analysis confirmed that patients with the G/G genotype had a significantly higher risk of poor response to AChEI treatment (odds ratio =10.310; 95% confidence interval, 1.510-70.362). Haplotype analysis revealed significant differences in haplotype frequency distribution between these groups. CONCLUSION: FOXO1 may influence the clinical response to AChEIs in AD patients.