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Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescence markers p16 and p21, accompanied by reductions in SA-β-gal- and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.

Tracheal hemangioma is a very rare benign vascular tumor. Few cases of tracheal hemangioma in children are reported in the literature. Chronic cough is the main symptom of the disease; however, hemoptysis is rarely reported as a symptom of tracheal hemangioma in children. Here, we report a case of tracheal hemangioma in an eight-year-old girl admitted to our pediatric department for recurrent hemoptysis. Routine biological and radiological investigations were normal. Diagnosis was made using computed tomography and bronchoscopy. Beta-blocker therapy was not efficient. Bronchoscopic treatment by electrical excision enables complete recovery. Tracheal hemangioma should be considered a cause of recurrent hemoptysis when routine biological and radiological investigations are negative., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Upregulated signal flow through RAS and the mitogen-associated protein kinase (MAPK) cascade is the unifying mechanistic theme of the RASopathies, a family of disorders affecting development and growth. Pathogenic variants in more than 20 genes have been causally linked to RASopathies, the majority having a dominant role in promoting enhanced signaling. Here, we report that SPRED2 loss of function is causally linked to a recessive phenotype evocative of Noonan syndrome. Homozygosity for three different variants-c.187C>T (p.Arg63 ∗ ), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs ∗ 95)-were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behavior. When overexpressed in cells, all variants were unable to negatively modulate EGF-promoted RAF1, MEK, and ERK phosphorylation, and time-course experiments in primary fibroblasts (p.Leu100Pro and p.Leu381Hisfs ∗ 95) documented an increased and prolonged activation of the MAPK cascade in response to EGF stimulation. Morpholino-mediated knockdown of spred2a and spred2b in zebrafish induced defects in convergence and extension cell movements indicating upregulated RAS-MAPK signaling, which were rescued by expressing wild-type SPRED2 but not the SPRED2 Leu381Hisfs ∗ 95 protein. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome. These features, in part, characterize the phenotype of Spred2 -/- mice. Our findings identify the second recessive form of Noonan syndrome and document pleiotropic consequences of SPRED2 loss of function in development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Malignant tumors of the temporal bone are rare. They include a wide histological variety. They are mostly primary tumors with an estimated incidence of 0.8-1.0 per 1,000,000 inhabitants per year [1]. Metastases form an uncommon subgroup. The clinical features of these temporal bone metastases are nonspecific and predominantly consist of hearing loss, vertigo, facial palsy, tinnitus, headache, otalgia or otorrhoea [2]. The aim of our publication is to report a rare case of metastasis in the temporal bone as initial manifestation of lung cancer. Our patient was a 44-year-old man who presented for a right mastoid swelling with a grade VI right facial nerve palsy. Imaging and biopsy confirmed the diagnosis of small cell lung carcinoma petrous metastasis. The treatment was palliative. An osteolytic lesion of the temporal bone in an elderly patient may fit with a primary tumor of the temporal bone. It must, also, suggest the diagnosis of metastasis. The malignant tumor most frequently responsible is breast cancer, but lung cancer must also be considered in smoking patients.

Tuberculosis, a human infectious disease caused by Mycobacterium tuberculosis ( M.tb ), is still a major cause of morbidity and mortality worldwide. The success of M.tb as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which M.tb maintains a persistent infection in a "silent" granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However, M.tb effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The E arly S ecreted A ntigenic T arget 6 kDa or ESAT-6, has been implicated in the virulence and pathogenesis of tuberculosis. Here, we investigated roles of ESAT-6 in MΦ differentiation and polarization. We found that treatment of human monocytes with ESAT-6 did not interfere with differentiation of M1 MΦs. However, ESAT-6 promoted differentiation of M0 and M2 MΦs toward the M1 phenotype, as indicated by secretion of pro-inflammatory cytokines IL-6, IL-12, and TNF-α, and induction of a typical M1 transcriptional signature. Interestingly, we found that ESAT-6 switched terminal full activation of M1 polarized MΦs to the M2 phenotype. Indeed, in the pro-inflammatory M1 MΦs, ESAT-6 was able to inhibit IL-12 and TNF-α secretion and stimulate that of IL-10. Moreover, gene expression profiling of these cells showed that ESAT-6 induced downregulation of M1 MΦ cell surface molecules CD80 and CD86 , transcription factors IRF5 and c-MAF , cytokines IL-12, IL-10 , and IL-6 , as well as chemokines CXCL10 and CXCL1 . Overall, our findings suggest ESAT-6 as being one of the effectors used by M.tb to induce the pro-inflammatory M1 phenotype at the primo-infection; a prerequisite step to promote granuloma formation and subsequently drive the phenotype switch of MΦ polarization from M1 to M2 at a later stage of the infection. Our study improves current knowledge regarding mechanisms of virulence of M.tb and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.

Purpose: The transcription factor Krüppel-like factor 6 (KLF6) regulates various cellular functions, such as metabolism, cell proliferation, and differentiation. KLF6 plays a key role in the development and progression of multiple human cancers., Methods: Fifty primary biopsies and 10 normal nasopharyngeal mucosae were used to analyze by RT-QPCR the expression and the copy number of wtKLF6 and the spliced variants (KLF6-SV1, KLF6-SV2, and KLF6-SV3) in Tunisian patients with nasopharyngeal carcinoma. The expression analysis of E-cadherin and cyclin D1 was conducted by RT-QPCR and Western blot, respectively., Results: The wtKLF6 was significantly downexpressed in tumors compared to normal tissues ( p = 0.0015), whereas KLF6-SV1 and KLF6-SV2 were overexpressed in tumors compared to wtKLF6 and KLF6-SV3 ( p < 0.0001). Copy number variation was reduced in tumors compared to normal tissues ( p = 0.0071). Interestingly, KLF6-SV1 is associated with the juvenile form ( p = 0.0003) which is more aggressive than the adult form of NPC. Furthermore, the oncogenic variant KLF6-SV1 was overexpressed in tumors lacking the expression of E-cadherin ( p = 0.0022) suggesting its role in metastasis and tumor progression. The wtKLF6 is associated negatively with cyclin D1 in tumor tissues ( p = 0.048)., Conclusion: The wtKLF6 was downexpressed in contrast with the oncogenic variants. Overexpression of KLF6-SV1 is associated with young patients, and loss of E-cadherin suggests that this variant correlated with the aggressiveness of NPC.

We investigated human leukocyte antigen (HLA) profiles for Tunisians with nasopharyngeal carcinoma (NPC), their families, and a sample of unrelated healthy Tunisians in order to identify HLA specificities associated with familial NPC. HLA-A, -B, and -DRB1 typing was successful for 36 NPC patients, 72 unaffected family members, and 130 community controls, and the chi square or Fisher exact test was used to compare allele frequencies between cases and controls. We observed a consistent protective effect of HLA-DRB1*10 on NPC development. However, none of the NPC patients or their family members had a positive result for this HLA marker (0% vs 9.2% in controls, P = 0.047). In addition, HLA-A*26 was probably an induction marker, as its allelic frequency was significantly higher among NPC patients than among controls (P = 0.003) and among NPC patients than among at-risk family members (P = 0.067). Logistic regression analysis of the joint effect of selected HLA specificities showed that HLA-A*26 and HLA-A*30 were co-associated and have an important effect on NPC risk. Despite the small size of our cohort, we showed that HLA-A*26-A*30 and HLA-DRB1*10 might be predictive markers for NPC screening of Tunisian families with a high risk of NPC.

Leishmania-specific cytotoxic T cell response is part of the acquired immune response developed against the parasite and contributes to resistance to reinfection. Herein, we have used an immune-informatic approach for the identification, among Leishmania major potentially excreted/secreted proteins previously described, those generating peptides that could be targeted by the cytotoxic immune response. Seventy-eight nonameric peptides that are predicted to be loaded by HLA-A*0201 molecule were generated and their binding capacity to HLA-A2 was evaluated. These peptides were grouped into 20 pools and their immunogenicity was evaluated by in vitro stimulation of peripheral blood mononuclear cells from HLA-A2+-immune individuals with a history of zoonotic cutaneous leishmaniasis. Six peptides were identified according to their ability to elicit production of granzyme B. Furthermore, among these peptides 3 showed highest affinity to HLA-A*0201, one derived from an elongation factor 1-alpha and two from an unknown protein. These proteins could constitute potential vaccine candidates against leishmaniasis.

Background: During a blood meal, female sand flies, vectors of Leishmania parasites, inject saliva into the host skin. Sand fly saliva is composed of a large variety of components that exert different pharmacological activities facilitating the acquisition of blood by the insect. Importantly, proteins present in saliva are able to elicit the production of specific anti-saliva antibodies, which can be used as markers for exposure to vector bites. Serological tests using total sand fly salivary gland extracts are challenging due to the difficulty of obtaining reproducible salivary gland preparations. Previously, we demonstrated that PpSP32 is the immunodominant salivary antigen in humans exposed to Phlebotomus papatasi bites and established that humans exposed to P. perniciosus bites do not recognize it., Methodology/principal Findings: Herein, we have validated, in a large cohort of 522 individuals, the use of the Phlebotomus papatasi recombinant salivary protein PpSP32 (rPpSP32) as an alternative method for testing exposure to the bite of this sand fly. We also demonstrated that screening for total anti-rPpSP32 IgG antibodies is sufficient, being comparable in efficacy to the screening for IgG2, IgG4 and IgE antibodies against rPpSP32. Additionally, sera obtained from dogs immunized with saliva of P. perniciosus, a sympatric and widely distributed sand fly in Tunisia, did not recognize rPpSP32 demonstrating its suitability as a marker of exposure to P. papatasi saliva., Conclusions/significance: Our data indicate that rPpSP32 constitutes a useful epidemiological tool to monitor the spatial distribution of P. papatasi in a particular region, to direct control measures against zoonotic cutaneous leishmaniasis, to assess the efficiency of vector control interventions and perhaps to assess the risk of contracting the disease.

The nature of effector cells and the potential immunogenicity of Leishmania major excreted/secreted proteins (LmES) were evaluated using peripheral blood mononuclear cells (PBMCs) from healed zoonotic cutaneous leishmaniasis individuals (HZCL) and healthy controls (HC). First, we found that PBMCs from HZCL individuals proliferate and produce high levels of IFN-γ and granzyme B (GrB), used as a marker of activated cytotoxic T cells, in response to the parasite antigens. IFN-γ is produced by CD4(+) T cells, but unexpectedly GrB is also produced by CD4(+) T cells in response to stimulation with LmES, which were found to be as effective as soluble Leishmania antigens to induce proliferation and cytokine production by PBMCs from immune individuals. To address the question of regulatory T cell (Tregs) involvement, the frequency of circulating Tregs was assessed and found to be higher in HZCL individuals compared to that of HC. Furthermore, both CD4(+)CD25(+) and CD4(+)CD25(-) T cells, purified from HZCL individuals, produced IFN-γ and GrB when stimulated with LmES. Additional experiments showed that CD4(+)CD25(+)CD127(dim/-) Tregs were involved in GrB production. Collectively, our data indicate that LmES are immunogenic in humans and emphasize the involvement of CD4(+) T cells including activated and regulatory T cells in the immune response against parasite antigens.

Mediterranean area (MA) represents a zone of intermediate incidence (1-5/100,000) for NPC, the highest frequency being observed in North Africa (NA) where it is characterized by a bimodal age repartition due to a first adolescence peak. In MA and NA, NPC remain diagnosed at advanced stages which impact poorly on overall and disease-free survival. It's therapy in MA followed the progresses and standardisation of protocols, based on concomitant chemoradiotherapy (CCRT) alone or preceded by induction chemotherapy (ICT) in advanced (N2-3, T3-4) stages, while localized cases are managed irradiation alone. NPC overall an disease-free survival improved, due to the use of combined chemo and radiotherapy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Papillary thyroid carcinoma is the most common form of differentiated thyroid carcinoma. It is generally confined to the neck with or without spread to regional lymph nodes. Metastatic thyroid carcinomas are uncommon and mainly include lung and bone. Metastases involving oral and maxillofacial region are extremely rare. We described a case of malar metastasis revealing a follicular variant of papillary thyroid carcinoma, presenting with pain and swelling of the left cheek in a 67-years-old female patient with an unspecified histological left lobo-isthmectomy medical history. To our knowledge, this is the first recorded instance of a malar metastasis from a follicular variant of papillary thyroid carcinoma.