Hematopoietic stem cell transplantation corrects the immunologic abnormalities associated with immunodeficiency-centromeric instability-facial dysmorphism syndrome.

Immunodeficiency-centromeric instability-facial dysmorphism syndrome, characterized by variable immunodeficiency, centromeric instability, and facial anomalies caused by epigenetic dysregulation resulting in hypomethylation, is caused in many patients by mutations in DNMT3B, a DNA methyltransferase gene; associated infections are a major cause of serious sequelae and death. Hematopoietic stem cell transplantation may improve the clinical course in immunodeficiency-centromeric instability-facial dysmorphism syndrome. We report 3 unrelated patients with persistent infections and intestinal complications who successfully underwent hematopoietic stem cell transplantation after nonmyeloablative or myeloablative conditioning regimens using HLA-matched donors. In all cases, donor chimerism led to resolution of intestinal complications and infections, growth improvement, and correction of the immunodeficiency

Testing the acoustic adaptation hypothesis with vocalizations from three mongoose species

International audienceAcoustic signals degrade and attenuate as they propagate through the environment, thus transmitting information with lower efficiency. The acoustic adaptation hypothesis (AAH) states that selection should shape the vocalizations of a species to maximize transmission through their habitat. A specific prediction of the AAH is that vocalizations will transmit better when emitted in their native habitat versus non-native habitats. We tested this prediction using vocalizations of three mongoose species that dwell in structurally different habitats: banded mongooses, Mungos mungo, dwarf mongooses, Helogale parvula, and meerkats, Suricata suricatta. Representative vocalizations of the three species were broadcast and rerecorded in each habitat at six distances from the source. Rerecorded vocalizations were compared to nondegraded calls through spectrogram correlation. Using generalized linear mixed models, we then quantified the differences in transmission fidelity of each species' vocalizations. Overall, we found partial support for the AAH within the mongoose family: habitat type strongly affected sound transmission, but depending on the species, vocalizations did not always transmit best in their native habitat, suggesting various degrees of acoustic adaptation. Vegetation cover within habitat type was also found to have a significant influence on the transmission properties of vocalizations. In addition, we found evidence that by changing their behaviour, either by producing vocalizations at different amplitudes or by choosing a specific calling location, mongooses can reduce sound degradation and attenuation over distance, thereby enhancing their communication efficiency. Our work highlights how habitat features may be key determinants of vocalization structure in mongooses, and is generalizable to other species living in similar conditions. It also suggests that, given a species and habitat, other selective pressures might prevail and limit acoustic adaptation in animal communication systems. Finally, our study provides insights into how mammals can adjust their vocal behaviour to compensate for environmental constraints on the transmission of their vocalizations. © 2022 The Author(s

Phenotype-genotype correlation : challenge of intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses

BACKGROUND: Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses shows microscopic features indistinguishable from colorectal cancer. Our aim was to verify whether the morphologic resemblances mirror genetic profile similarities. METHODS: Twenty consecutive surgically treated ITAC cases, previously investigated for p16(INK4a) and TP53, were investigated for hMLH1, hMSH2, and beta-catenin immunoreactivity, and for adenomatous polyposis coli (APC), K-ras, and BRAF gene mutations. RESULTS: One case was immunonegative for both hMLH1 and hMSH2, and 12 tumors (40%) revealed a strong beta-catenin overexpression. No BRAF and APC truncating mutations were identified, whereas K-ras mutations were detected in 9 ITACs (50%). CONCLUSIONS: Our data confirm the phenotypic similarities at the genetic level between colorectal cancer and ITACs showing deregulation of K-Ras/BRAF and loss of heterozygosity (LOH) of chromosome 18q. By contrast, both frequency rate and type of inactivation of the APC-beta-catenin pathway differ in the 2 tumors, suggesting different gatekeeper events in the early development of ITAC (p16(INK4a) and TP53) and colorectal cancer (APC)

Midterm analysis of the seleXys cup with ceramic inlay

Background: Ceramic-on-ceramic (CoC) articulations in total hip replacement (THR) has been accepted as giving reliable mid-term results; however recent studies have reported higher revision rates of some implants. This study analyses the nationwide results of the seleXys TPS cup and the Bionit2 liner (Mathys, Bettlach, Switzerland) with respect to implant survival, cause for revision and mortality rates compared to other CoC articulations using the same stem. Methods: Utilising the New Zealand Joint Registry, we compared the seleXys TPS cup with Bionit2 liner used with an uncemented Twinsys femoral stem to every other uncemented CoC THR using the same stem. Multivariate analysis was used to determine the effects of patient age, gender, ASA score and implant head size on these rates. Results: Between 2006 and 2013 a total of 1035 seleXys THRs were performed on 862 patients. The comparison group had 375 THRs on 280 patients. There were 77 revisions (1.4/100 component years) in the study group and two in the comparison group (0.12/100 component years). Overall hazards ratio for revision was 12.22 times higher and female gender was associated with an increased risk (hazards ratio 1.77). Causes for revision were disturbing noises (23.4%), acetabular loosening (20.8%), and fracture of the liner (18.2%). Mortality rates were not significantly different (P = .567). Conclusions: The seleXys TPS cup with the Bionit2 ceramic inlay coupling has an unacceptably high failure rate. We recommend avoiding this implant coupling and would advise that patients treated with this implant need close clinical and radiological follow-up

The clinical and biological overlap between nijmegen breakage syndrome and Fanconi anaemia

Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome, is characterized clinically by developmental abnormalities, growth retardation, progressive bone marrow failure, pancytopenia, and pronounced cancer predisposition. Nijmegen Breakage Syndrome (NBS) is a related disorder that shares overlapping clinical features, principally, developmental delay, microcephaly, and cancer predisposition. The diagnosis has relied on chromosomal instability following exposure to DNA cross-linking agents in FA and to ionizing radiation (IR) in NBS. We describe two patients who clinically had FA, but showed sensitivity to both DNA cross-linking agents and ionizing radiation, and who were found to have a rare mutation in the NBS gene. The importance of genetic diagnosis with respect to treatment and prognosis is discussed

Prediction of TP53 status for primary cisplatin, fluorouracil, and leucovorin chemotherapy in ethmoid sinus intestinal-type adenocarcinoma

Purpose: To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC). Patients and Methods: Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome. Results: Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P 64 .0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061). Conclusion: The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation

TP53, p14(ARF), p16(INK4a) and H-RAS gene molecular analysis in intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses

Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon tumor associated with occupational exposure to dusts of different origin. Few investigations addressed molecular alterations in ITAC mainly focused on TP53, K-ras and H-ras gene mutations. The occurrence of TP53, p14(ARF) and p16(INK4a) deregulation and H-ras mutations was investigated in 21 consecutive and untreated ITACs cases, 17 with known professional exposure. No H-ras mutations were found. In patients with known exposure, cumulative evidence of TP53 or p14(ARF) alterations accounted for 88% and the evidence of p16(INK4a) alterations for 65%, respectively. TP53 mutations were present in 44% of the ITACs, consisted of G:C-->A:T transitions in 86%, and involved the CpG dinucleotides in 50% of the cases. LOH at the locus 17p13 and an uncommon high rate of p53 stabilization were detected in 58% and 59% of the cases, respectively. p14(ARF) and p16(INK4a) promoter methylation accounted for 80% and 67% respectively, and LOH at the locus 9p21 occurred in 45% of the cases. Interestingly, all dust-exposed tumors with p16(INK4a) alterations shared TP53 or p14(ARF) deregulation. The present results show a close association of this occupational tumor with TP53, p14(ARF) and p16(INK4a,) gene deregulation. Given the important role that these genes play in cell growth control and apoptosis, the knowledge of ITAC genetic profile may be helpful in selecting more tailored treatments