The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One of the critical features of the ccRCC TIME is the presence of infiltrating immune cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. Among these cells, CD8+ T cells are particularly important in controlling tumor growth by recognizing and killing cancer cells. However, the TIME of ccRCC is also characterized by an immunosuppressive environment that hinders the function of immune cells. Several mechanisms contribute to the immunosuppressive nature of the ccRCC TIME. For instance, ccRCC cells produce cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-ß), which suppress immune cell activation and promote the differentiation of regulatory T cells (Tregs). Tregs, in turn, dampen the activity of effector T cells and promote tumor growth. In addition, ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function. In addition, other immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3), also contribute to the immunosuppressive milieu of the ccRCC TIME. Finally, the hypoxic and nutrient-poor microenvironment of ccRCC can stimulate the production of immunosuppressive metabolites, such as adenosine and kynurenine, which further impair the function of immune cells. Understanding the complex interplay between tumor cells and the immune system in the ccRCC TIME is crucial for developing effective immunotherapies to treat this disease.

Self-Report of the perception of stress and signs of bruxism generated during the pandemic in student of the health area / Autoinforme de la percepción de estrés y signos de bruxismo derivados de la pandemia en estudiantes del área de la salud

Abstract Bruxism is the repetitive muscle-mandibular behavior characterized by clenching and/or grinding of the teeth, which reflects the presence of one or more underlying conditions or factors. The objective of this descriptive study was to determine the association between bruxism and stress self-perceived during the pandemic, as well as their frequency by gender and academic area. An interrogation and self-perceived stress scale PSS-14 were applied to students from the different areas of the Institute of Health Sciences (ICSa) to determine the presence or absence of stress and bruxism symptom, a Chi-square was used for the comparison between variables, considering a value of p0.005. ICSa students between 18 and 24 age perceive symptoms of bruxism and high levels of stress caused during the pandemic.

Resumen El bruxismo es el comportamiento músculo-mandibular repetitivo caracterizado por apretamiento y/o rechinamiento de los dientes, que refleja la presencia de una o varias condiciones o factores subyacentes. Se realizó un estudio descriptivo con el objetivo de determinar la asociación del nivel de estrés y síntomas de bruxismo autopercibidos durante la pandemia, así como su frecuencia por género y área académica. Se aplicó un interrogatorio y escala de estrés percibido PSS-14 a los estudiantes de las distintas áreas del Instituto de Ciencias de la Salud (ICSa) para determinar la presencia o ausencia de estrés y síntomas de bruxismo, se utilizó una Chi-cuadrada para la comparación entre variables, considerando significativo un valor de p0.0001. Los estudiantes de 18 a 24 años de edad del ICSa perciben síntomas de bruxismo y altos niveles de estrés originados durante la pandemia.

Y-box binding protein-1 is crucial in acquired drug resistance development in metastatic clear-cell renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a highly vascular tumor and patients with low risk metastatic RCC of clear-cell histological sub-type (mccRCC) are treated with tyrosine-kinase inhibitors (TKIs), sunitinib, as the first-line of treatment. Unfortunately, TKI resistance eventually develops, and the underlying molecular mechanism is not well understood. METHODS: RCC cell-line with metastatic clear-cell histology (Caki-1), and patient samples were analysed to identify the role of Y-box binding protein 1 (YB-1) and ATP-binding cassette sub-family B member 1 (ABCB-1) in acquired sunitinib-resistance development. Caki-1 was conditioned with increasing sunitinib doses to recapitulate acquired resistance development in clinics. Sunitinib-conditioned and wild-type Caki-1 were subjected to cell viability assay, scratch assay, chicken embryo chorioallantoic membrane engraftment and proteomics analysis. Classical biochemical assays like flow cytometry, immunofluorescent staining, immunohistochemical staining, optical coherence tomography imaging, Western Blot and RT-PCR assays were applied to determine the possible mechanism of sunitinib-resistance development and the effect of drug treatments. Publicly available data was also used to determine the role of YB-1 upregulation in ccRCC and the patients' overall survival. RESULTS: We demonstrate that YB-1 and ABCB-1 are upregulated in sunitinib-resistant in vitro, ex vivo, in vivo and patient samples compared to the sensitive samples. This provides evidence to a mechanism of acquired sunitinib-resistance development in mccRCC. Furthermore, our results establish that inhibiting ABCB-1 with elacridar, in addition to sunitinib, has a positive impact on reverting sunitinib-resistance development in in vitro, ex vivo and in vivo models. CONCLUSION: This work proposes a targeted therapy (elacridar and sunitinib) to re-sensitize sunitinib-resistant mccRCC and, possibly, slow disease progression.

Identification of gene signature for treatment response to guide precision oncology in clear-cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC) is a common therapy resistant disease with aberrant angiogenic and immunosuppressive features. Patients with metastatic disease are treated with targeted therapies based on clinical features: low-risk patients are usually treated with anti-angiogenic drugs and intermediate/high-risk patients with immune therapy. However, there are no biomarkers available to guide treatment choice for these patients. A recently published phase II clinical trial observed a correlation between ccRCC patients' clustering and their response to targeted therapy. However, the clustering of these groups was not distinct. Here, we analyzed the gene expression profile of 469 ccRCC patients, using featured selection technique, and have developed a refined 66-gene signature for improved sub-classification of patients. Moreover, we have identified a novel comprehensive expression profile to distinguish between migratory stromal and immune cells. Furthermore, the proposed 66-gene signature was validated using a different cohort of 64 ccRCC patients. These findings are foundational for the development of reliable biomarkers that may guide treatment decision-making and improve therapy response in ccRCC patients.

Effect of cytomegalovirus infection and leukocyte immunoglobulin like receptor B1 polymorphisms on receptor expression in peripheral blood mononuclear cells.

Leukocyte immunoglobulin like receptor B1 (LILRB1) plays a significant role in a number of infectious, autoimmune, cardiovascular, and oncologic disorders. LILRB1 expression varies between individuals and may be associated with polymorphisms on the regulatory region of the LILRB1 gene, as well as to previous cytomegalovirus infection. In this study, the contribution of these two factors to LILRB1 expression in peripheral blood mononuclear cells of healthy young adults was analyzed. LILRB1 expression in NK cells, T cells, B cells and monocytes was significantly stronger in individuals who had had cytomegalovirus infection than in those who had not (P < 0.001, P < 0.001, P < 0.01, and P < 0.001, respectively). Overall, no differences in LILRB1 expression were observed between individuals with and without GAA haplotypes of the LILRB1 regulatory region. However, when analyzed according to cytomegalovirus infection status, significant differences in LILRB1+ NK cells were observed. A higher proportion of LILRB1+ cells was found in GAA+ than in GAA- individuals who had not been infected (P < 0.01), whereas GAA- individuals had a larger proportion of LILRB1+ cells than GAA+ individuals who were cytomegalovirus positive (P < 0.01). In conclusion, cytomegalovirus infection has a major effect on LILRB1 expression in NK and other mononuclear cells and polymorphisms in the LILRB1 regulatory region appear to have a modulatory influence over this effect.

Development of Novel Single-Chain Antibodies against the Hydrophobic HPV-16 E5 Protein.

The human papilloma virus type 16 infects genital mucosa with high prevalence in the oncogenesis of cervical and oropharyngeal cancers. The E5 protein of this virus is a small hydrophobic protein, whose expression generally decreases as the infection progresses to malignancy. These characteristics point to a role of E5 in the establishment of HPV infection and the initiation into cell transformation. The study of the HPV-16 E5 functions has been hindered because of the lack of antibodies. Detection is very difficult because of its hydrophobic nature, membrane location, and very low levels of expression. Thus, the objective of this study was to select single-chain antibodies against the full size E5 protein, which was coexpressed with maltose-binding protein. We report that the E5 protein was recognized by the antibody and was validated in W12 cells by fluorescent microscopy, including a colocalization with one of its host substrates. The use of this antibody could increase our knowledge about the functions of the oncogenic HPV-16 E5 protein during the earliest stages of keratinocyte infection in human.

Intensive Care Unit Admission and Death Rates of Infants Admitted With Respiratory Syncytial Virus Lower Respiratory Tract Infection in Mexico.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common etiology for acute respiratory infection hospital admissions in young children. Case fatality rates for hospitalized patients range between 0% and 3.4%. Recent reports indicate that deaths associated with RSV are uncommon in developed countries. However, the role of this virus as a current cause of mortality in other countries requires further examination. METHODS: Children with RSV infection admitted between May 2003 and December 2014 to a level 2 specialty hospital in Mexico were included in this analysis. Underlying risk factors, admission to the intensive care unit (ICU) and condition on discharge were assessed to determine the ICU admission and death rates associated to RSV infection. RESULTS: We analyzed data of 1153 patients with RSV infection in whom information regarding underlying illnesses and discharge status was available. Sixty patients (5.2 %) were admitted to the ICU and 12 (1.04 %) died. Relevant underlying conditions were present in 320 (27.7%) patients. Infants with underlying respiratory disorders (excluding asthma) and a history of prematurity had high ICU admission rates (17.1% and 13.8%, respectively). Mortality rates were highest for infants with respiratory disease (excluding asthma) (7.3%), cardiovascular diseases (5.9%) and neurologic disorders (5.3%). The ICU admission and death rates were higher in infants <6 months of age than in other age groups. CONCLUSIONS: The ICU admission rate and mortality rate in Mexican infants hospitalized with RSV infection were 5.2% and 1%, respectively. Mortality rates were high in infants with respiratory, cardiovascular and neurologic disorders.

NK cell immunophenotypic and genotypic analysis of infants with severe respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection in infants. Reduced numbers of NK cells have been reported in infants with severe RSV infection; however, the precise role of NK cells during acute RSV infection is unclear. In this study the NK and T cell phenotypes, LILRB1 gene polymorphisms and KIR genotypes of infants hospitalized with RSV infection were analyzed. Compared to controls, infants with acute RSV infection showed a higher proportion of LILRB1+ T cells; in addition, a subgroup of infants with RSV infection showed an increase in LILRB1+ NK cells. No differences in NKG2C, NKG2A, or CD161 expression between RSV infected infants and controls were observed. LILRB1 genotype distribution of the rs3760860 A>G, and rs3760861 A>G single nucleotide polymorphisms differed between infants with RSV infection and healthy donors, whereas no differences in any of the KIR genes were observed. Our results suggest that LILRB1 participates in the pathogenesis of RSV infection. Further studies are needed to define the role of LILRB1+ NK in response to RSV and to confirm an association between LILRB1 polymorphisms and the risk of severe RSV infection.

Pandemic influenza A(H1N1) 2009 and respiratory syncytial virus associated hospitalizations.

OBJECTIVES: To determine the contribution of influenza and respiratory syncytial virus (RSV) as the cause of lower respiratory tract infection (LRTI) associated hospitalizations during the first year of the influenza A(H1N1) 2009 pandemic and to assess the severity of illness during the second pandemic wave. METHODS: Patients admitted with LRTI from April 2009 through March 2010 were assessed for the presence of influenza and RSV. Pandemic influenza virus was detected by means of a nested RT-PCR assay and/or the CDC's real time-PCR protocol. RSV was detected using a one-step RT-PCR assay. The characteristics of patients admitted during the first and second pandemic outbreaks were compared. RESULTS: 657 patients with LRTI were admitted during the study period. Pandemic influenza virus was detected in 180 and RSV in 133. Influenza was the most common cause of infection in adults, while RSV was more common in children. There were no differences in disease severity between the first and second pandemic outbreaks. CONCLUSIONS: Pandemic influenza virus was associated to increased numbers of hospitalizations and deaths; particularly in adults. The severity of the first and second pandemic outbreaks was similar. RSV continues to be the main pathogen responsible for hospitalizations in young children.