Car T Cells in Solid Tumors: Overcoming Obstacles.

Chimeric antigen receptor T cell (CAR T cell) therapy has emerged as a prominent adoptive cell therapy and a therapeutic approach of great interest in the fight against cancer. This approach has shown notorious efficacy in refractory hematological neoplasm, which has bolstered its exploration in the field of solid cancers. However, successfully managing solid tumors presents considerable intrinsic challenges, which include the necessity of guiding the modified cells toward the tumoral region, assuring their penetration and survival in adverse microenvironments, and addressing the complexity of identifying the specific antigens for each type of cancer. This review focuses on outlining the challenges faced by CAR T cell therapy when used in the treatment of solid tumors, as well as presenting optimizations and emergent approaches directed at improving its efficacy in this particular context. From precise localization to the modulation of the tumoral microenvironment and the adaptation of antigen recognition strategies, diverse pathways will be examined to overcome the current limitations and buttress the therapeutic potential of CAR T cells in the fight against solid tumors.

Chronic kidney disease (CKD) and chronic kidney insufficiency (CKI) diagnosing equation in cirrhotic patients.

Cirrhotic patients can develop acute kidney injury (AKI), and chronic kidney disease (CKD). Therefore, renal functional evaluation is crucial in cirrhotic patients. However, serum creatinine and urea levels, as well as measured or estimated glomerular filtration rate is not reliable renal functional markers in these patients compared to other patient groups. In the present study, four original equations are designed and tested for screening chronic kidney disease (CKD) and chronic kidney insufficiency (CKI) in stable cirrhotic patients. MATERIAL & METHOD: estimated GFR (CKD-EPI creatinine and cystatin equations) were recorded in 175 adult stable patients suffering from cirrhosis, and these patients were classified as presenting or not CKD and CKI after evaluation by two independent nephrologists. Based on these data, the variables with the significant discriminating capability to identify CKD and CKI (based on creatinine and cystatin) were detected by applying the Student's t-test for two independent groups, later confirmed by the lambda test of Wilks, in order to obtain the renal function equations. RESULTS: CKD equation (creatinine) = 7.094238-0.043104 × CKD-EPI creatinine - 0.057537 × haematocrit. CKD equation (cystatin) = 8.375074-0.117218 × CKD-EPI cystatin. CKI equation (creatinine) = 0.428389-0.043214 × CKD-EPI creatinine +0.183051 × Child-Pugh score + 0.050162 × age (in years). CKI equation (cystatin) = 9.169579-0.139319 × CKD-EPI cystatin. CONCLUSION: Simple and reliable equations have been obtained for screening chronic kidney disease and chronic kidney insufficiency in cirrhotic patients.

Obesity and Oral Health: The Link Between Adipokines and Periodontitis.

Periodontitis is a chronic inflammatory disease of the periodontium, or the supportive tissues around the tooth. This disease has been related to different risk factors, such as the presence of plaque and calculus, tobacco smoking, low socioeconomic status, and the immune state of the host. Importantly, the chronic inflammatory environment generated by periodontitis may lead to tooth loss and diverse systemic complications, such as cardiovascular disease, osteoarthritis and metabolic disease. Recent investigations have supported the role of obesity as a risk factor for periodontitis. Furthermore, studies have found obesity to compromise healing after periodontal therapy; however, the mechanisms underlying this association are not well understood. Proteins called 'adipokines' could be the factor linking obesity to periodontitis. Adipokines are bioactive molecules with hormonal properties and a structure similar to cytokines produced by the adipose tissue. Although adipokines have both pro-and anti-inflammatory effects, the shift towards pro-inflammatory actions occurs when the adipose tissue becomes pathological, as observe in the progression of conditions such as obesity or adiposopathy. This article reviews the role of adipokines in the pathophysiology and progression of periodontitis by focusing on their impact on inflammation and the molecular mechanisms through which adipokines contribute to the onset and development of periodontitis.

Pregnancy-Associated Atypical Hemolytic Uremic Syndrome: A Case Report with MCP Gene Mutation and Successful Eculizumab Treatment.

Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare condition characterized by microangiopathic hemolytic anemia and kidney injury from thrombotic microangiopathy. P-aHUS occurs in approximately 1 in 25,000 pregnancies and is strongly related to complement dysregulation and pregnancy-related disorders, such as preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome, resulting in adverse perinatal and fetal outcomes. Complement dysregulation in P-aHUS is commonly attributed to genetic mutations or autoantibodies affecting complement factors, including CFH , CFI , and MCP. We present a case of a 25-year-old primigravida who experienced severe preeclampsia and HELLP syndrome followed by the development of complicated P-aHUS during the early postpartum period. The patient exhibited severe clinical manifestations, including hypertensive emergency, central nervous system involvement, renal impairment, and microangiopathic hemolytic anemia. Timely initiation of eculizumab therapy resulted in successful disease remission. Further genetic analysis revealed a likely rare pathogenic MCP gene variant.

Mortality Rate and Acute Kidney Injury Prevalence Reduction in COVID-19 Critical Patients Treated with Hemoperfusion.

Introduction: Coronavirus disease 2019 (COVID-19) induces organic damage mainly through the patient's immune overreaction. Hemoperfusion (HPF) can remove inflammatory cytokines and can reduce the negative effects of cytokine storm in COVID-19. We compared the mortality rate, inflammatory response, and acute kidney injury (AKI) prevalence among patients suffering from respiratory insufficiency secondary to COVID-19 treated with and without HPF with HA330 cartridge. Methods: Mortality rate, serum creatinine, and ferritin values were compared between patients suffering from respiratory insufficiency secondary to COVID-19 who received conventional treatment and another group of patients who additionally received four sessions of HPF with HA330. Results: Of 116 patients suffering from acute respiratory insufficiency secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), one group (n: 84) received support treatment and the other group (n: 32) additionally received HPF with HA330 cartridge. Both groups had no renal disease and similar age and comorbidities at admission, except for obesity and mechanical ventilation requirement, which were significantly higher in the HPF group. Mortality rate (61% vs. 31%, P: 0.008), serum creatinine (1.4 vs. 0.5 mg/dl, P < 0.001), and post-HPF serum ferritin (2868 vs. 1675, P < 0.001) were significantly lower in the HPF group. Conclusion: Mortality rate, serum ferritin, and AKI were significantly reduced in critical COVID-19 patients who received HPF with HA330 cartridge than in those who did not receive it. These results were obtained despite the HPF group risk factors, such as obesity and mechanical ventilation, worsening its prognosis.

Frailty status improvement after kidney transplantation.

INTRODUCTION: Frailty is a clinical syndrome characterized by a decrease in strength, resistance and body physiological condition, making the individual more vulnerable, and increasing his/her risk of dependence and death. Kidney transplant (KT) is currently the best end-stage renal disease therapeutic alternative for certain individuals. Frailty status occurs in approximately 20% of KT patients. Thus, it was evaluated if there would be any change in frailty status level in a population of adult patients on chronic HD after receiving KT. MATERIAL AND METHOD: A cross-sectional study was conducted on a population of adult hemodialysis patients (n: 57), with the objective of evaluating if there was a significant change in their clinical frailty score (CFS) after 6 months of KT. For the statistical analysis, the Student's t-test, and the test of statistical significance between two proportions were applied. RESULTS: Mean CFS before KT was 4 (vulnerable), and after KT was 3 (robust). CFS value was significantly lower after KT (p value < 0.01). CONCLUSION: A significant improvement was found between pre- and post-transplant clinical frailty scores in hemodialysis adult patients.

Decreasing microbiota-derived uremic toxins to improve CKD outcomes.

Chronic kidney disease (CKD) is set to become the fifth-leading global cause of death by 2040. This illustrates the many unknowns regarding its pathogenesis and therapy. A key unknown relates to the therapeutic impact of the interaction between CKD and the gut microbiome. The normal gut microbiome is essential for body homeostasis. There is evidence for multiple interactions between the microbiota and CKD-its causes, comorbidities and therapeutic interventions-that are only starting to be unraveled. Thus uremic retention products, such as urea itself, modify the gut microbiota biology and both dietary and drug prescriptions modify the composition and function of the microbiota. Conversely, the microbiota may influence the progression and manifestations of CKD through the production of biologically active compounds (e.g. short-chain fatty acids such as butyrate and crotonate) and precursors of uremic toxins. The present review addresses these issues and their relevance for novel therapeutic approaches ranging from dietary interventions to prebiotics, probiotics, synbiotics and postbiotics, to the prevention of the absorption of microbial metabolites and to increased clearance of uremic toxins of bacterial origin through optimized dialysis techniques or blockade of tubular cell transporters.

Immune Lymphocyte Infiltrate and its Prognostic Value in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) occurs more frequently in young (<50 years) non-Hispanic black and Hispanic/Latina women. It is considered the most aggressive subtype of breast cancer, although, recently, immune infiltrate has been associated with long-term survival, lower risk of death and recurrence, and response to neoadjuvant chemotherapy. The aim of this review was to evaluate the clinical impact of the immune infiltrate in TNBC by discussing whether its prognostic value varies across different populations. A comprehensive systematic search in databases such as PubMed and Web of Science was conducted to include papers focused on tumor-infiltrating lymphocytes (TILs) in TNBC in different population groups and that were published before January 2021. TNBC patients with higher levels of TILs had longer overall survival and disease-free survival times compared with TNBC patients with low TIL levels. Similar results were observed for CD4+, CD8+ TIL populations. On the other hand, patients with high TIL levels showed a higher rate of pathological complete response regardless of the population group (Asian, European, and American). These results altogether suggest that TIL subpopulations might have a prognostic role in TNBC, but the underlying mechanism needs to be elucidated. Although the prognosis value of TILs was not found different between the population groups analyzed in the revised literature, further studies including underrepresented populations with different genetic ancestries are still necessary to conclude in this regard.

Glomerular Diseases in the Colombian Caribbean: Data from the Colombian Nephropathy Registry (NEFRORED®).

Our study aimed to describe the glomerular diseases, both primary glomerular disease (PGD) and secondary glomerular disease (SGD) in the Colombian Caribbean based on the first regional Colombian Nephropathy Registry (NEFRORED®). A descriptive and retrospective study of adult patients with glomerular diseases from the Colombian Caribbean region was made. All diagnoses by renal biopsy with light microscopy and immunofluorescence obtained between January 2008 and June 2018 were recorded. Eight hundred and seventy-one renal biopsies were obtained. The main clinical indication for biopsy was nephritic syndrome (36%). SGD was more frequent than PGD (55% vs. 45%). Within SGD group, lupus nephritis (LN) was the most frequent etiology (83%). Within PGD group, membranous nephropathy (33%) and focal segmental glomerulosclerosis (FSGS) (19%) were the most common glomerular diseases. At a 24-month follow-up, the patients with FSGS and paraproteinemia-mediated glomerular disease had the worst renal survival prognosis. This is the first Colombian Nephropathy Registry in a Caribbean population, demonstrating a high predominance of SGD due to LN.

Comparative Analysis of In-House RT-qPCR Detection of SARS-CoV-2 for Resource-Constrained Settings.

We developed and standardized an efficient and cost-effective in-house RT-PCR method to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated sensitivity, specificity, and other statistical parameters by different RT-qPCR methods including triplex, duplex, and simplex assays adapted from the initial World Health Organization- (WHO) recommended protocol. This protocol included the identification of the E envelope gene (E gene; specific to the Sarvecovirus genus), RdRp gene of the RNA-dependent RNA polymerase (specific for SARS-CoV-2), and RNase P gene as endogenous control. The detection limit of the E and the RdRp genes were 3.8 copies and 33.8 copies per 1 µL of RNA, respectively, in both triplex and duplex reactions. The sensitivity for the RdRp gene in the triplex and duplex RT-qPCR tests were 98.3% and 83.1%, respectively. We showed a decrease in sensitivity for the RdRp gene by 60% when the E gene acquired Ct values > 31 in the diagnostic tests. This is associated with the specific detection limit of each gene and possible interferences in the protocol. Hence, developing efficient and cost-effective methodologies that can be adapted to various health emergency scenarios is important, especially in developing countries or settings where resources are limited.

Atypical hemolytic uremic syndrome in the Colombian Caribbean: its particular characteristics.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a rare and genetically mediated systemic disease most often caused by uncontrolled and chronic complement activation that leads to systemic thrombotic microangiopathy, renal and extra-renal damage. MATERIALS AND METHODS: This is descriptive, retrospective and multicenter study, which reports demographic, clinical, laboratory, and genetic characteristics, as well as their treatment response and outcome of 20 aHUS patients diagnosed between 2014 and 2018. RESULTS: Most patients were female adults (75%) and 30% were associated to pregnancy/postpartum, 15% to autoimmune disease, and 65% to infections. Gastrointestinal involvement (75%) was the most frequent extra-renal organ damage. Antenatal mortality and mortality rate were 5% and 10%, respectively. 25% of the patients progressed to end-stage renal disease. In 4/8 of patients treated within 1 week of presentation, eculizumab treatment restored multi-organ function after 4 weeks of treatment. CFH (37%) and CFI (25%) mutations were the most frequent. CONCLUSION: This is the first series of aHUS cases of Colombian Caribbean region which reports the clinical and epidemiological characteristics of this condition in this region.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i): renal implications.

Type 2 diabetes mellitus (DM2) is a chronic condition that affects more than 400 million individuals worldwide. In DM2 patients, an appropriate glycemic control slows the onset and delays the progression of all its micro and macrovascular complications. Even though there are several glucose-lowering drugs, only approximately half of patients achieve glycemic control, while undesirable adverse effects (e.g., low serum glucose) normally affect treatment. Therefore, there is a need for new types of treatments. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have just been developed for treating DM2. Renal hyperfiltration as a marker of increased intraglomerular pressure in diabetic patients, and the role of renin-angiotensin-aldosterone system (RAAS) in this phenomenon have been studied. Nevertheless, RAAS blockade does not completely reduce hyperfiltration or diabetic renal damage. In this sense, the contribution of renal tubular factors to the hyperfiltration state, including sodium-glucose cotransporter (SGLT), has been currently studied. SGLT2i reduce proximal tubular sodium reabsorption, therefore increasing distal sodium delivery to the macula densa, causing tubule-glomerular feedback activation, afferent vasoconstriction, and reduced hyperfiltration in animal models. In humans, SGLT2i was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients suffering from type 1 diabetes mellitus. In DM2 clinical trials, SGLT2 is associated with significant hyperfiltration and albuminuria reduction. The aim of this article is to compile the information regarding SGLT2i drugs, emphasizing its mechanism of renal repercussion.

Impact of frailty and viral load on acute kidney injury evolution in patients affected by Coronavirus Disease 2019.

This paper describes the main characteristics of coronavirus diseases 2019 (COVID-19) patients suffering from acute kidney injury (AKI) assisted at a high complexity clinic in Barranquilla, Colombia. The patients included in this study (n = 48) were those with a positive diagnosis of COVID-19 confirmed by polymerase chain reaction detection of severe acute respiratory syndrome coronavirus 2, who had developed AKI during their hospital stay. Serum and urine parameters, as well as patient's viral load and clinical frailty scale (CFS) were recorded. A statistical analysis of the recorded parameters, such as comparisons, and correlations between variables of interest, were explored. The prevalence of COVID-19 induced AKI was 41%, being the majority of them classified as AKI network classification 3, with a renal replacement therapy requirement of 29%, and an associated mortality of 73%. AKI patients' mortality showed a significant positive correlation (33%) with patients' CFS score but not with their viral load. COVID-19 induced AKI significantly correlated with patients' frailty status but not to their viral load.

Optimizing dialysis dose in the context of frailty: an exploratory study.

INTRODUCTION: Frailty is a multicausal syndrome characterized by a decrease in strength, resistance and physiological function, which makes the individual vulnerable and dependent, and increases his/her mortality. This syndrome is more prevalent among older individuals, and chronic kidney disease patients, particularly those on dialysis. Dialysis dose is currently standardized for hemodialysis (HD) patients regardless of their age and functional status. However, it has been postulated that the dialysis dose required in older patients, especially frail ones, should be lower, since it could increase their degree of frailty. Then, the purpose of this study was to evaluate if there would be a correlation between the dose of Kt/V and the degree of frailty in a population of adult patients on HD. MATERIALS AND METHODS: A cross-sectional study with 82 patients on HD in Barranquilla (Colombia) and Lobos (Argentina) was conducted. Socio-demographic and laboratory data, as well as dialysis doses (Kt/V) were recorded and scales of fragility, physical activity, gait and grip strength were applied. Then these data were correlated by a Spearman's correlation and a logistic regression. RESULTS: CFS, social isolation, physical activity, gait speed, and prehensile strength tests were outside the reference ranges in the studied group. No significant correlation was found between dialysis dose and all the above mentioned functional tests. However, a significant and inverse correlation between physical activity and CFS was documented (score - 1.41 (CI - 2.1 to - 0.7). CONCLUSION: No significant correlation was documented between Kt/V value and different parameters of the frailty status, but this status correlated significantly and inversely with physical activity in this group. Frailty status in hemodialysis patients was significantly higher in older individuals, although young individuals were not exempt from it.

Osmotic diuresis in chronic kidney disease: its significance and clinical utility.

INTRODUCTION: The kidneys contribute to maintain plasma osmolality in normal range by achieving the adequate daily osmolar urine excretion (DOUE). An equation has been described for estimating the expected daily urine volume necessary to excrete the osmolar load required to keep serum osmolality in normal range. According to this equation, a difference between real and expected daily osmolar diuresis (DOD) can be obtained, being normally this difference value zero (± 500 cc). However, a positive DOD difference signifies a reduced urine concentration capability, while a negative DOD difference signifies a reduced urine dilution capability. Therefore, we decided to originally investigate how DOUE, and DOD difference are modified through the different stages of CKD. MATERIALS AND METHODS: 61 patients suffering from CKD (stages I-V) secondary to glomerulopathies were studied. Creatinine clearance (CrCl), DOUE, and difference between real and expected DOD were obtained from each patient. Besides, correlation (Spearman) between CrCl and DOUE, and between CrCl and real-expected DOD difference were also obtained. RESULTS: Spearman correlation between CrCl and DOUE was positive and significant (Spearman's ρ = 0.63, p < 0.0001). In addition, CKD patients who were not able to achieve the minimal DOUE required (600 mOsm/day) were mostly those with CrCl < 40 mL/min. Spearman correlation between CrCl and real-expected DOD difference was negative and significant (Spearman's ρ = - 0.4, p < 0.0013). Additionally, abnormal DOD difference (> 500 cc) was found in CKD patients with CrCl < 80 mL/min/1.73 m2. CONCLUSION: Daily osmolar urine excretion, and difference between real and expected daily osmolar diuresis are simple and significant clinical parameter which can be useful to easily evaluate urine concentration-dilution capability (tubular function) in CKD patients.

The Importance of Tubular Function in Chronic Kidney Disease.

Glomerular filtration rate (GFR) and proteinuria-albuminuria are the renal functional parameters currently used to evaluate chronic kidney disease (CKD) severity. However, tubular secretion is another important renal functional parameter to be taken into account since proximal tubule (PT) secretion, in particular, is a crucial renal mechanism for endogenous organic cations, anions and drug elimination. The residual diuresis is a relevant survival predictor in patients on dialysis, since their urine is produced by the glomerular and tubular functions. It has been hypothesized that drugs which up-regulate some renal tubular transporters could contribute to uremic toxin excretion, and nephroprevention. However, if tubular transporters' down-regulation observed in CKD patients and experimental models is a PT adaptation to avoid intracellular accumulation and damage from uremic toxins, consequently the increase of toxin removal by inducing tubular transporters' up-regulation could be deleterious to the kidney. Therefore, a deeper understanding of this phenomenon is currently needed. In conclusion, tubular function has an important role for endogenous organic cations, anions and drug excretion in CKD patients, and a deeper understanding of its multiple mechanisms could provide new therapeutic alternatives in this population.

Integrated analysis of microRNA regulation and its interaction with mechanisms of epigenetic regulation in the etiology of systemic lupus erythematosus.

The aim of this study was to identity in silico the relationships among microRNAs (miRNAs) and genes encoding transcription factors, ubiquitylation, DNA methylation, and histone modifications in systemic lupus erythematosus (SLE). To identify miRNA dysregulation in SLE, we used miR2Disease and PhenomiR for information about miRNAs exhibiting differential regulation in disease and other biological processes, and HMDD for information about experimentally supported human miRNA-disease association data from genetics, epigenetics, circulating miRNAs, and miRNA-target interactions. This information was incorporated into the miRNA analysis. High-throughput sequencing revealed circulating miRNAs associated with kidney damage in patients with SLE. As the main finding of our in silico analysis of miRNAs differentially expressed in SLE and their interactions with disease-susceptibility genes, post-translational modifications, and transcription factors; we highlight 226 miRNAs associated with genes and processes. Moreover, we highlight that alterations of miRNAs such as hsa-miR-30a-5p, hsa-miR-16-5p, hsa-miR-142-5p, and hsa-miR-324-3p are most commonly associated with post-translational modifications. In addition, altered miRNAs that are most frequently associated with susceptibility-related genes are hsa-miR-16-5p, hsa-miR-374a-5p, hsa-miR-34a-5p, hsa-miR-31-5p, and hsa-miR-1-3p.

Applying art to scientific research: reasons for using an original method. / Aplicación del arte a la investigación científica: fundamentos de un método original para su utilización.

Art, by virtue of its symbolic power, may function as a cognitive instrument and even as an aid in the scientific research process, especially in the phase of hypothesis generation and data analysis given its ability to induce creative and intuitive thinking. In this article, we propose a method to put such concept into practice based on the exposure of scientists to collective artistic activities in protected settings, a methodology developed from the experiences described by renowned artists and scientists.

El arte en virtud de su poder simbólico puede funcionar como instrumento cognitivo y contribuir, incluso, al proceso de investigación científica, sobre todo, en sus etapas de generación de hipótesis y discusión de datos, debido a su capacidad inductora del pensamiento intuitivo y creativo. En el presente artículo, se propone un método para llevar a la práctica esta concepción, basado en la exposición de los científicos a actividades artísticas colectivas en ambientes protegidos, metodología diseñada a partir de experiencias relatadas por destacados artistas y científicos.

Profiling analysis of circulating microRNA in peripheral blood of patients with class IV lupus nephritis.

Renal involvement in Systemic Lupus Erythematous (SLE) patients is one of the leading causes of morbidity and a significant contributor to mortality. It's estimated that nearly 50% of SLE individuals develop kidney disease in the first year of the diagnosis. Class IV lupus nephritis (LN-IV) is the class of lupus nephritis most common in Colombian patients with SLE. Altered miRNAs expression levels have been reported in human autoimmune diseases including lupus. Variations in the expression pattern of peripheral blood circulating miRNAs specific for this class of lupus nephritis could be correlated with the pathophysiological status of this group of individuals. The aim of this study was to evaluate the relative abundance of circulating microRNAs in peripheral blood from Colombian patients with LN-IV. Circulating miRNAs in plasma of patients with diagnosis of LN-IV were compared with individuals without renal involvement (LNN group) and healthy individuals (CTL group). Total RNA was extracted from 10 ml of venous blood and subsequently sequenced using Illumina. The sequences were processed and these were analyzed using miRBase and Ensembl databases. Differential gene expression analysis was carried out with edgeR and functional analysis were done with DIANA-miRPath. Analysis was carried out using as variables of selection fold change (≥2 o ≤-2) and false discovery rate (0.05). We identified 24 circulating microRNAs with differential abundance between LN-IV and CTL groups, fourteen of these microRNAs are described for the first time to lupus nephritis (hsa-miR-589-3p, hsa-miR-1260b, hsa-miR-4511, hsa-miR-485-5p, hsa-miR-584-5p, hsa-miR-543, hsa-miR-153-3p, hsa-miR-6087, hsa-miR-3942-5p, hsa-miR-7977, hsa-miR-323b-3p, hsa-miR-4732-3p and hsa-miR-6741-3p). These changes in the abundance of miRNAs could be interpreted as alterations in the miRNAs-mRNA regulatory network in the pathogenesis of LN, preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of LN.