Nuclear Factor-kappa B as a Resistance Factor to Platinum-Based Antineoplasic Drugs

Platinum drugs continue to be major chemotherapy drugs for cancer treatment. Nevertheless, acquired or intrinsic resistance to these compounds is common in human tumors. One important mechanism for this resistance is the avoidance of cells entering the apoptotic pathway. Nuclear factor-kappa B (NF-kappa B, NF-κB) is a pleiotropic transcription factor key in determining the death threshold of human cells. This factor is important in the final response of cells to platinum drugs, as exemplified by in vitro and in vivo models showing that inhibition of NF-κB sensitizes cancer cells to the effects of these drugs. New approaches focusing on the inhibition of NF-κB could help to minimize or even eliminate intrinsic or acquired resistance to platinum drugs

Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia

BackgroundA heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC).MethodsA population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff’s spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained.ResultsA total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed.ConclusionsThe identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL

Is there something else besides the proapoptotic AVPI-segment in the Smac/DIABLO protein?

In mammals, apoptosis is the main mechanism to eliminate unwanted cells, securing tissue homeostasis and consequently maintaining the health in the organism. Classically, apoptosis culminates with the activation of caspases, which are enzymes that display cysteine protease activity to degrade specific substrates implied in essential cellular processes. This process is highly regulated. A key regulation mechanism is mediated by the Inhibitor of Apoptosis Proteins (IAPs) family members, which inhibit the activated forms of caspases through physical interaction with them. Smac/DIABLO, a mitochondrial protein that is translocated to the cytoplasm in apoptotic conditions, derepresses the IAP-mediated caspase inhibition through physical interaction with IAPs. The first four amino acids (AVPI) of Smac/DIABLO mediate the interaction with IAPs and subsequent apoptosis induction. This interaction has lead to the creation of small molecules mimicking the AVPI segment for potential anticancer therapy. Nevertheless, several studies have pointed out the existence of AVPI-independent functions of Smac/DIABLO. The aim of this review was to provide a landscape of these underestimated AVPI-independent biological functions that have been observed using different approaches, such as the study of endogenous splice variant isoforms and truncated and mutated artificial proteins

Gene regulation by BCL3 in a cervical cancer cell line

BCL3 is a putative proto-oncogene deregulated in haematopoieitic and solid tumours. It has been suggested that its oncogenic effects could be mediated, at least in part, by inducing proliferation and inhibiting cell death. To provide more insight into the mediators of these effects, we used an unbiased approach to analyse the mRNA expression changes after knocking-down BCL3 using specific shRNAs. One hundred eighty genes were up-regulated and sixty-nine genes were down-regulated after knocking down BCL3. Function analyses showed enrichment in genes associated with cellular growth and proliferation, cell death and gene expression. We found that STAT3, an important oncogene in human cancer, was the central node of one of the most significant networks. We validated STAT3 as a bona fide target of BCL3 by additional interference RNA and in silico analyses of previously reported lymphoma patients

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in <i>FANCG</i>

Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population

Table_1_Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia.xlsx

BackgroundA heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC).MethodsA population-based case-control study was conducted. Children ResultsA total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (pConclusionsThe identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.</p