Papers by Alfredo Minguela Puras
Journal of Clinical Medicine
B-cell activating factor (BAFF) system signaling is critical for B-cell homeostasis, effector fun... more B-cell activating factor (BAFF) system signaling is critical for B-cell homeostasis, effector functions, and tolerance maintenance in transplants, but it has not been studied in kidney transplant recipients (KTRs). The aim was to analyze the changes in BAFF system expression in KTRs with/without acute rejection (AR/NAR). The BAFF system expression was analyzed by qPCR in 40 KTRs. A meta-analysis of BAFF system expression and histological renal damage was identified by the Chronic Allograft Damage Index (CADI) and performed from the GEO database. Proliferation-inducing ligand (APRIL) expression increased at three- and six-months post-KT (p = 0.014 and p < 0.001). B-cell maturation antigen (BCMA) expression increased at six-months post-KT (p = 0.038). BAFF expression remained stable in NAR-KTRs, but was increased in CADI concerning the No-CADI group at one year (p = 0.008). BCMA expression increased in the CADI group at one- (p = 0.001) and six-years post-KT (p = 0.024). At three m...
Acute Lymphoblastic Leukaemia (ALL) is the most frequent paediatric cancer. Modern therapies have... more Acute Lymphoblastic Leukaemia (ALL) is the most frequent paediatric cancer. Modern therapies have improved survival rates, but approximately 15-20 % of patients relapse. At present, patients' risk of relapse are assessed by projecting high-dimensional flow cytometry data onto a subset of biomarkers and manually estimating the shape of this reduced data. Here, we apply methods from topological data analysis (TDA), which quantify shape in data via features such as connected components and loops, to pre-treatment ALL datasets with known outcomes. We combine these fully unsupervised analyses with machine learning to identify features in the pre-treatment data that are prognostic for risk of relapse. We find significant topological differences between relapsing and non-relapsing patients and confirm the predictive power of CD10, CD20, CD38, and CD45. Further, we are able to use the TDA descriptors to predict patients who relapsed. We propose three prognostic pipelines that readily ex...
Improved therapies in multiple myeloma (MM) have forced a constant risk stratification update, fi... more Improved therapies in multiple myeloma (MM) have forced a constant risk stratification update, first Durie-Salmon, then international scoring systems (ISS), next revised-ISS (RISS) including high-risk cytogenetic abnormalities (HRCAs) such as del(17p) and t(4;14), and now R2-ISS including 1q21 gain has been proposed. Predictive value of 1q21 gain by itself or in concurrence with other cytogenetic abnormalities is evaluated in 737 real-world plasma cell neoplasm (PCN) patients under current therapies. Ten-year progression-free survival (10y-PFS) rates for patients with 2, 3 and >3 copies of 1q21 were 72.2%, 42.5% and 43.4% (P<1.1×10-17). Cox regression analysis confirmed that 1q21 gain was an independent prognostic factor for PFS (HR=1.804, P<0.0001, Harrell C-statistic =0.7779±0.01495) but not for OS (P=0.131). Gain of 1q21 was strongly associated with hypodiploidy (38.8% vs. 7.0%, P=1.3×10-22), hyperdiploidy (44.1% vs. 16.4%, P=1.6×10-13), HRCAs (12.6% vs. 3.5%, 1.8×10-5),...
Heliyon, 2019
DOCK10, a guanine-nucleotide exchange factor (GEF) for Rac1 and Cdc42 Rho GTPases whose expressio... more DOCK10, a guanine-nucleotide exchange factor (GEF) for Rac1 and Cdc42 Rho GTPases whose expression is induced by interleukin-4 (IL-4) in B cells, is involved in B cell development and function according to recent studies performed in Dock10-knockout (KO) mice. To investigate whether DOCK10 is involved in regulation of the transcriptome, changes in the gene expression profiles (GEPs) were studied by microarray in three cellular models: DOCK10 expression induced by doxycycline (dox) withdrawal in a stable inducible HeLa clone, DOCK10 expression induced by transient transfection of 293T cells, and wild type (WT) versus KO mouse spleen B cells (SBC). In all three systems, DOCK10 expression determined moderate differences in the GEPs, which were functionally interpreted by gene set enrichment analysis (GSEA). Common signatures significantly associated to expression of DOCK10 were found in all three systems, including the upregulated targets of HOXA5 and the SWI/SNF complex, and EGF signaling. In SBC, Dock10 expression was associated to enrichment of gene sets of Cmyb, integrin, IL-4, Wnt, Rac1, and Cdc42 pathways, and of cellular components such as the immunological synapse and the cell leading edge. Transcription of genes involved in these pathways likely acts as a feedforward mechanism downstream of activation of Rac1 and Cdc42 mediated by DOCK10. Interestingly, a senescence gene set was found significantly associated to WT SBC. To test whether DOCK10 is related to
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation, Jan 28, 2018
The aim of this study was to analyze alcoholic cirrhosis in women who were to undergo liver trans... more The aim of this study was to analyze alcoholic cirrhosis in women who were to undergo liver transplant, including their biochemical and clinical characteristics, main complications, survival rates, and main causes of death compared with men with alcoholic cirrhosis. Our study included 400 patients with alcoholic cirrhosis, which we divided according to sex and viral infections. Biochemical parameters and the presence and degree of ascites and encephalopathy, liver function status, and liver rejection and survival rates were analyzed from 1 to 10 years and the main cause of death at 10 years. Patients with nonviral alcoholic cirrhosis and liver transplant had significantly better survival rates (84.1%) at 1 year versus those with viral alcoholic cirrhosis (74.5%; P = .036). Men with nonviral alcoholic cirrhosis (14%) and women with hepatitis C virus (29%) had the lowest short-term survival rates. In long-term survival analysis, the lowest rate was observed in women with nonviral alco...
Transplant Immunology, 2005
In this retrospective study, we analyzed the effect of the presence of anti-donor preformed alloa... more In this retrospective study, we analyzed the effect of the presence of anti-donor preformed alloantibodies in 268 liver allograft transplants. Crossmatches were performed by complement-dependent cytotoxicity (CDC) assay and HLA antibody screening by flow cytometry (FlowPRA). Positive anti-donor crossmatch was detected in 5.2% of transplants. Acute rejection frequency in +CDC crossmatch patients was not different from that observed in -CDC crossmatch patients. None of the patients transplanted with +CDC crossmatch developed chronic rejection, but they showed a significantly lower allograft survival rate, and the majority of them had allograft failures before the end of the first post-transplant year, mainly within the 3 first months. Indeed, positive FlowPRA determination was concordant with data from the CDC assay. In conclusion, these findings show a direct correlation between the presence of anti-donor preformed antibodies and a poor allograft survival in liver transplant.
Transplantation Journal, 2013
Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) li... more Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial. KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups. KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05), with KIR2DL3 and KIR2DS1 exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4 significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3 recipients and donors having C1 ligands (log rank, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107-0.962; P=0.042), whereas KIR2DS1 and KIR2DS4 recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156-27.369; P=0.002 for KIR2DS1; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267-11.365; P=0.017 for KIR2DS4). This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4/C ligands also influence short-term graft survival.
Transplant Immunology, 2008
The CTLA4 molecule is a homolog for CD28, and both molecules and their common ligands (CD80 and C... more The CTLA4 molecule is a homolog for CD28, and both molecules and their common ligands (CD80 and CD86) constitute the B7/CD28-CTLA4 co-stimulatory pathway for T cells activation. The CTLA4-ligand interaction has an inhibitory effect on T cell activation and might contribute to peripheral tolerance. A recently described CT60 A/G polymorphism affects the production of soluble CTLA4 and is strongly associated with immune-mediated diseases and with allogenic stem cell transplantation outcome. Thus, we examined this marker on liver transplant outcome by a PCR-RFLP method. The CT60 G allele was significantly associated with acute rejection (Pc=0.038; OR=1.49; AR vs. NAR). Patients who lacked this allele had the lowest risk of acute rejection development. Allograft survival data did not show statistical differences between genotypes. In conclusion, CT60 A/G dimorphism within the 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-UTR of CTLA4 gene, which encodes for reduced sCTLA4 production, influence acute rejection development in liver transplantation.
The Journal of Immunology, 2003
Journal of Cranio-Maxillofacial Surgery, 1997
Nine cases of salivary duct carcinoma were reviewed clinically, histologically and immunohistoche... more Nine cases of salivary duct carcinoma were reviewed clinically, histologically and immunohistochemically, with special evaluation of biomarkers with prognostic significance (p53, Ki67, c-erbB-2 and DNA content). Eight tumours occurred in the parotid gland and one in the submandibular gland. The average age of the patients (8 males and 1 female) was 62.8 years (range = 47-74 years). Tumour size ranged from 1 to 6 cm (mean = 3.46 cm). Recurrences were found in 33.3% (3 patients), regional metastases in 44.4% (4 patients) and systemic metastases in 33.3% (3 patients). Three patients died of their disease (median survival = 12.3 months), one is alive with the disease (follow-up of 222 months) and 5 are alive without evidence of disease (mean follow-up of 75 months), p53 protein nuclear immunostaining was positive in 66.6% and c-erbB-2 overexpression was observed in 100% of the tumours. Ki 67 positivity ranged from 6.75% to 47.5% of turnout cells (mean = 21.3%). DNA aneuploidy was found in 4 tumours (44.4%) and DNA diploidy in 5 (55.5%). Our results seem to indicate that Ki67 immunostaining can be useful in the evaluation of the biological behaviour of these tumours, as well as the presence of a high proliferative index of aneuploid cells and the presence of distant metastases.
Human Immunology, 2001
Human leukocyte antigen (HLA) study in Murcian individuals was performed in order to provide info... more Human leukocyte antigen (HLA) study in Murcian individuals was performed in order to provide information of their historical origins and relationships with other Iberian and Mediterranean populations. HLA class I and class II alleles were determined in 173 unrelated Caucasoid donors from Murcia Region in the Southeast of Spain by serologic and DNA based polymerase chain reaction (PCR) typing. Class I antigen and class II allele frequencies of our series were not very different to those found in Spaniards. The analysis of extended haplotypes showed that the three haplotypes most frequent in our population were respectively, A29-B44-Cwb-DRB1*0701-DRB4*0101-DQA1*0201-DQB1*0202, A1-B8-Cw7-DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201 and A30-B18-Cw5-DRB1*0301-DRB3* 0101-DQA1*0501-DQB1*0201. They were followed by A26-B38-Cwb-DRB1*1301-DRB3*0202-DQA1*0103-DQB1*0603, which could point to an ancestral relationship between Murcian and Portuguese Iberian populations , and by A2-B7-Cw7-DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 also present in all Iberian Peninsula populations. Allelic frequencies, populations distance dendrogram and correspondence analysis were used to study the relationships between Murcian and other populations. The closest relation was observed with Spaniards and Portuguese, followed in decreasing order by French, Italians, Algerians, Germans, Catalans, Basques, Cretans, Sardinians, and Greeks. Thus, Murcian population seems to belong to the European genetic pool, revealing a lesser genetic distance with the North Africans and the rest of populations from the Iberian Peninsula.
Human Immunology, 1999
Membrane HLA class-I expression (mHLA-I), soluble HLA class-I antigens (sHLA-I) and interleukin (... more Membrane HLA class-I expression (mHLA-I), soluble HLA class-I antigens (sHLA-I) and interleukin (IL)-10 are different factors implicated in the special acceptance of liver allograft. In this study, pre-and post-operative levels of mHLA-I in peripheral blood lymphocytes (PBL) and serum sHLA-I were analyzed in 86 liver transplants, immunosuppressed with Cyclosporine-A, methylprednisolone and azathioprine, and classified into acute-rejection (AR, n ϭ 28) and non-acute-rejection (NAR, n ϭ 58) groups. Serum IL-10 was studied in 47 recipients (AR-group, n ϭ 16 and NAR-group, n ϭ 31). Pre-transplant values of mHLA-I and sHLA-I showed a bimodal distribution (high/low) in NAR-recipients, but in AR-patients were mainly included in the low expression/secretion zone (mHLA-I, p Ͻ 0.02 and sHLA-I, p Ͻ 0.05). Consequently, average pre-transplant mHLA-I (868 Ϯ 109 versus 998 Ϯ 123, p Ͻ 0.05) and sHLA-I (1.3 Ϯ 0.4 versus 2.02 Ϯ 0.7 g/ml, p Ͻ 0.01) was lower in the AR-than in the NAR-group. After transplant both parameters decreased in the NAR-group, but increased in AR-recipients previous to and on rejection diagnosis day. Additionally, serum IL-10 levels were significantly higher (p Ͻ 0.01) in the NAR than in the AR-group during the first 24 h post-transplant. In conclusion, low pre-transplant mHLA-I and sHLA-I levels pre-dispose liver recipients to acute rejection, whereas early post-transplant increases of serum IL-10 appear to be related to a good liver allograft acceptance.
Human Immunology, 2008
Major histocompatibility complex class I-related chain A (MICA) is located at 46 kb centromeric o... more Major histocompatibility complex class I-related chain A (MICA) is located at 46 kb centromeric of HLA-B. It is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, T␥␦ and T CD8 lymphocytes. Data on MICA polymorphism in different populations are still limited. Our aim was to establish allelic diversity of MICA gene and linkage disequilibrium with HLA-B in our population. DNA was obtained from 154 unrelated healthy individuals from the Murcia region in southeastern Spain. HLA-B genotyping was performed using polymerase chain reaction (PCR)sequence-specific oligonucleotide probes and allele-specific PCR-sequence-specific primers, and MICA genotyping by using PCR-sequence-specific oligonucleotide probes. A total of 19 MICA alleles were detected on this study. MICA*008 was the most frequent allele (25.3%), followed by MICA*002 (16.1%), MICA*004 (14.9%), MICA*001 (7.8%), MICA*009 and MICA*016 (7.1%), and MICA*010 (4.6%). Eleven alleles had frequencies of Ͻ1%. In the haplotype analysis, MICA*008-B*0702 was found to be the most common, followed by MICA*004-B*4403 and MICA*001-B*1801, MICA*002-B*3501, MICA*008-B*4402, MICA*004-B*4901, MICA*008-B*0801, and MICA*002-B*3801. The frequency of MICA*010-B*1501, MICA*008-B*1302, MICA*015-B*4501 , and MICA*008-B*4001 was remarkable inasmuch as these two last haplotypes have not been reported in Spanish population. Indeed, MICA*016 linked to B*1402 has also not been reported in the literature. In conclusion, the allelic diversity in our population is similar to other Caucasian populations; however we found a series of less frequent alleles, in addition to as-yet-undescribed haplotypic associations in other populations of Caucasian origin.
Human Biology, 2001
HLA-DQB1*0302 allele frequency is increased in liver graft recipients with acute rejection. We in... more HLA-DQB1*0302 allele frequency is increased in liver graft recipients with acute rejection. We investigated polymorphism in the upstream regulatory regions (URRs) of the DQB1 gene to determine whether polymorphism in the DQB1 promoter region influences liver graft acceptance. A combination of typing protocols based on the polymerase chain reaction were used in 103 first-time liver transplants and 108 healthy Spanish controls. The QBP3.21 allele frequency and QBP3.21-DQB1*0302 haplotype were significantly different in recipients with acute rejection compared to those with good graft acceptance and to controls. Of major interest for acute rejection development are the promoter "splits" of DQB1*0302 (QBP3.21, QBP3.22, and QBP3.3 alleles), which are in linkage disequilibrium with DQB1*0302. The promoter splits were equally distributed in all groups. Thus, although there are significant differences in the frequencies of the QBP alleles and QBP-DQB1 haplotypes between recipients with and without acute rejection and controls, the composition of these haplotypes is essentially the same in all groups. In conclusion, our data show that the polymorphism in the DQB1 promoter region does not clearly influence liver graft acceptance, and, as occurs in other populations, QBP alleles exhibit strong linkage disequilibrium with the DQB1 locus.
Cancer, 1998
There is a considerable degree of subjectivity and, therefore, substantial interobserver and intr... more There is a considerable degree of subjectivity and, therefore, substantial interobserver and intraobserver disagreement in the diagnosis and grading of dysplastic lesions in Barrett&amp;amp;amp;amp;amp;amp;#39;s esophagus (BE). The aim of this study was to evaluate the usefulness of DNA flow cytometry and immunohistochemical staining for p53 protein as objective methods to complement the conventional histologic diagnosis of dysplasia in patients with this disease. The most common problems and the possible advantages of using these procedures are analyzed briefly in this article. Formalin fixed, paraffin embedded tissue from 55 patients diagnosed with BE were processed for flow cytometric measurements (ploidy and proliferation index) and p53 immunostaining. Both the cytometric data and the positivity of staining for p53 revealed a statistically significant increase throughout the following sequence: no dysplasia --&amp;amp;amp;amp;amp;amp;gt; indefinite for dysplasia --&amp;amp;amp;amp;amp;amp;gt; low grade dysplasia --&amp;amp;amp;amp;amp;amp;gt; high grade dysplasia --&amp;amp;amp;amp;amp;amp;gt; adenocarcinoma. There was also a highly significant correlation between the results of the cytometric study and the positivity of staining for p53. In the future, the use of this procedure could play an important role in the evaluation of patients with BE. Considering that staining for p53 is technically simple, economical, and quick, and the materials required are available to most pathology laboratories, this method appears to be a firm candidate for application as a biomarker in BE. The authors have shown that it is possible to obtain adequate results for cytometric analysis with small formalin fixed, paraffin embedded biopsies if a strict protocol for the acceptance of tissue samples and/or histograms is observed.
Brain, Behavior, and Immunity, 2012
Killer-cell immunoglobulin-like receptor (KIR) proteins are expressed on natural killer (NK) cell... more Killer-cell immunoglobulin-like receptor (KIR) proteins are expressed on natural killer (NK) cells and appear important in innate and adaptive immunity. There are about 14 KIR genes on chromosome 19q13.4, composed of those that inhibit and those that activate NK cell killing. Haplotypes have different combinations of these genes meaning that not all genes are present in a subject. There are two main classes of cognate human leukocyte antigen (HLA) ligands (HLA-Bw4 and HLA-C1/C2) that bind to the inhibitory/activating receptors. As a general rule, the inhibitory state is maintained except when virally infected or tumor cells are encountered; however, both increased activation and inhibition states have been associated with susceptibility and protection against numerous disease states including cancer, arthritis, and psoriasis. Utilizing DNA from 158 Caucasian subjects with autism and 176 KIR control subjects we show for the first time a highly significant increase in four activating KIR genes (2DS5, 3DS1, 2DS1 and 2DS4) as measured by chi square values and odds ratios. In addition, our data suggests a highly significant increase in the activating KIR gene 2DS1 and its cognate HLA-C2 ligand (2DS1 + C2; p = 0.00003 [Odds ratio = 2.87]). This information ties together two major immune gene complexes, the human leukocyte complex and the leukocyte receptor complex, and may partially explain immune abnormalities observed in many subjects with autism.
Actas Dermo-Sifiliográficas, 2005
El melanoma ha adquirido gran protagonismo en las últimas décadas, lo cual se justifica, además d... more El melanoma ha adquirido gran protagonismo en las últimas décadas, lo cual se justifica, además de por su agresividad, por el incremento exponencial de su incidencia 1 y porque se diagnostica en individuos cada vez más jóvenes 2 . Aunque el melanoma sólo representa el 3 % de las neoplasias malignas cutáneas, dicho tumor provoca el 65 % de las muertes por cáncer de piel y el 1,3 % del total de fallecimientos por cáncer en general 3 . También resultan inquietantes algunas predicciones que indican que uno de cada 75 sujetos nacidos en el año 2000 desarrollará un melanoma a lo largo de su vida 1 . El comportamiento biológico del melanoma es muy diferente al de otros cánceres de piel. Por ello, en los últimos años se han multiplicado los estudios para conocer mejor el mecanismo de acción y los efectos de los distintos componentes del sistema inmunitario en su defensa frente al melanoma 5 . Desde un punto de vista clínico, la intervención del sistema inmunitario
European Urology Oncology, 2019
Background: Bladder cancer (BC) is highly immunogenic. Bacillus Calmette-Guérin (BCG) immunothera... more Background: Bladder cancer (BC) is highly immunogenic. Bacillus Calmette-Guérin (BCG) immunotherapy offers the best results in non-muscle-invasive BC (NMIBC). Natural killer cells (NKcs) play decisive roles in BCG-mediated immune response and in general cancer immune-surveillance. Objective: To analyze killer-cell immunoglobulin-like receptors (KIRs), their human leukocyte antigen class-I (HLA-I) ligands, and the expression of DNAX Accessory Molecule-1 (DNAM-1/CD226) on peripheral blood (PB) NKcs, to identify useful predictive biomarkers in BC. Design, setting, and participants: KIR/HLA-ligand genotypes were compared between 132 BC, 201 other solid cancers, 164 plasma cell disorders, and 615 healthy Caucasoid controls. CD226 expression was evaluated by flow cytometry. Outcome measurements and statistical analysis: KIR/HLA-I interactions and CD226 expression on NKcs (CD226 high or CD226 low) were compared across study groups, cancer stages, treatments, and progression-free and overall survival of patients, using chi-square, analysis of variance/post hoc, Kaplan-Meier/log-rank, and regression analyses. Results and limitations: Three immunological risk groups were identified: low risk (KIR2DL1 À L2 + L3 À /C1C1 À and KIR2DL1 + L2 + L3 + /C1C1 +), intermediate risk (rest), and high risk (KIR2DL5 + /HLA-C*16 + and KIR2DL1 + L2 + L3 À), which displayed different 10-yr progression-free rates (83.3%, 48.6%, and 0%, respectively; p < 0.001) and survival rates (83.3%, 54.3%, and 6.2%, respectively; p < 0.001) for muscle-invasive T2/T4, and 10-yr progression-free rates (100%, 81.6%, and 50%, respectively; 1 C.F. Guillamón and L. Gimeno contributed equally to this article.
Archives of Medical Science
IntroductionThe molecular mechanisms underlying alcoholic liver fibrosis and cirrhosis are not co... more IntroductionThe molecular mechanisms underlying alcoholic liver fibrosis and cirrhosis are not completely understood. Hepatic fibrosis involves the interplay of diverse cells and factors, including hepatic stellate cells (HSCs), Kupffer, NK cells, and T-lymphocyte subsets. Killer-cell immunoglobulin-like receptors (KIR) are membrane receptors involved in mediation between NK and activated HSCs, regulating NK cell function through their interaction with HLA-I molecules. The aim of this study was to analyse the genetic association between KIR genes and the susceptibility to or protection from alcoholic cirrhosis (AC) in a cohort of male AC patients undergoing liver transplantation (LT) with and without concomitant viral infections.Material and methodsKIR genotyping was performed in nuclear DNA extracted from 281 AC patients and compared with 319 male controls.ResultsSignificant differences between total AC patients and healthy controls were only found in the case of KIR2DL2 and KIR2DS...
Dedicator-of-cytokinesis (DOCK), a family of guanine-nucleotide exchange factors (GEFs), comprise... more Dedicator-of-cytokinesis (DOCK), a family of guanine-nucleotide exchange factors (GEFs), comprises four subfamilies, named from A to D. DOCK-D comprises DOCK9, DOCK10, and DOCK11. The GEF activity involves translocation from the cytoplasm to the plasma membrane (PM), as assessed by the transfection of tagged proteins. However, the cellular localization of endogenous DOCK proteins is poorly understood. In this paper, to gain a better understanding of the role of the DOCK-D proteins, we studied their distribution between cytosol and nucleoplasm in 11 cell lines. DOCK-D proteins were distributed with variable cytosolic or nuclear predominance, although the latter was common for DOCK9 and DOCK11. These results suggest that the DOCK-D proteins may perform new nuclear functions, which remain to be discovered. Furthermore, we found that DOCK10 levels are increased by interleukin-4 (IL-4) in B-cell lymphoid neoplasms other than chronic lymphocytic leukemia (CLL) such as mantle cell lymphoma...
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Papers by Alfredo Minguela Puras