Concurrent NRAS-BRAF variants in metastatic colorectal cancer: a Tunisian case report.

Target therapy for metastatic colorectal cancer needs the determination of KRAS, NRAS, and BRAF mutation status to identify patients resistant to anti-EGFR treatment. RAS genes (KRAS/NRAS) are mutated in 40-60% of metastatic colorectal cancer and BRAF in 5-10%. The presence of a double mutation in RAS and BRAF is rare. Therefore, RAS and BRAF mutations were considered exclusive. Herein, we describe a novel concomitant NRAS/BRAF mutation identified in a series of 865 colorectal cancer patients.

An ode to multidisciplinarity: the 'Bacteria Orchestrate Life' international meeting.

If scientists stick to their research expertise without collaborating with other experts in different fields, it could stall the progress of their work in a world where interdisciplinary thinking and working should be second nature. Biologists are at the forefront of this trend. That is why a consortium formed by the faculty of sciences of Tunis El Manar University, Tunisia, the GetGenome Foundation and Learn and Win, decided to organise an international conference on bacteria, a perfect field for multidisciplinarity. For 3 days, from 14 to 16 December 2023, more than 200 interdisciplinary researchers and students of life sciences and more than 20 international speakers and trainers met at the faculty of sciences in Tunis, to discuss microbiology and bacteria from different horizons, from the most fundamental to the most imaginative, with a strong focus on technologies and discoveries. This Meeting Review describes the scientific event and highlights the main results of both the conferences and the practical sessions.

[McCune-Albright syndrome: a case report and literature review]. / Syndrome de McCune-Albright : à propos d'un cas et revue de la littérature.

McCune-Albright syndrome is an inherited disease characterized by the association of fibrous dystrophy of bone, café-au-lait skin spots and precocious puberty revealing endocrine hyperactivity. Genetically, this disease is due to a mutation of the Gs protein responsible for activation of adenylate cyclase with excessive production of cAMP. The particular morphology of café-au-lait spots should suggest early diagnosis. Its treatment depends on the endocrinopathy from which the patient suffers and the extent of the fibrous dysplasia. Bisphosphonates have proven their effectiveness on bone pain and the limitation of fibrous dysplasia. Surgery retains its place in complicated forms. We report a rare case of McCune-Albright syndrome complicated by a femur fracture in a 12-year-old girl and we discuss the clinical and paraclinical characteristics of this pathological entity.

Demystification and feasibility of CRISPR technology and gene editing in African laboratories.

Clustered regularly interspaced short palindromic repeats, or CRISPR, is a powerful molecular biology tool that is enabling high-quality genetic research and engineering. However, for practical reasons, but more specifically because of the lack of training and the rapid development of gene-editing technology, the technique is still not well established in African laboratories. For this reason, a consortium formed by the Institut Pasteur of Tunis and Learn and Win decided to organise an international conference and workshop on CRISPR technology in particular and gene editing in general, focusing on the low-budget model more appropriate to the African context. From 12 to 17 June 2023, more than 200 interdisciplinary researchers and students from the life sciences and more than 20 international speakers and trainers gathered at the Institut Pasteur in Tunis, Tunisia, for the First African Conference and Workshop on CRISPR to discuss the latest gene editing technologies and discoveries. This Meeting Review describes the scientific event and highlights the main outcomes of both the conferences and the practical sessions. The symposium was a real success and thrives to educate, train and network international and young scientists in the field of gene editing and gene engineering.

Tetraploidization Increases the Motility and Invasiveness of Cancer Cells.

Polyploidy and metastasis are associated with a low probability of disease-free survival in cancer patients. Polyploid cells are known to facilitate tumorigenesis. However, few data associate polyploidization with metastasis. Here, by generating and using diploid (2n) and tetraploid (4n) clones from malignant fibrous histiocytoma (MFH) and colon carcinoma (RKO), we demonstrate the migration and invasion advantage of tetraploid cells in vitro using several assays, including the wound healing, the OrisTM two-dimensional cell migration, single-cell migration tracking by video microscopy, the Boyden chamber, and the xCELLigence RTCA real-time cell migration. Motility advantage was observed despite tetraploid cell proliferation weakness. We could also demonstrate preferential metastatic potential in vivo for the tetraploid clone using the tail vein injection in mice and tracking metastatic tumors in the lung. Using the Mitelman Database of Chromosome Aberrations in Cancer, we found an accumulation of polyploid karyotypes in metastatic tumors compared to primary ones. This work reveals the clinical relevance of the polyploid subpopulation and the strategic need to highlight polyploidy in preclinical studies as a therapeutic target for metastasis.

Polo-like kinase inhibitor BI2536 induces eryptosis.

BI2536 is potent inhibitor of polo-like kinases PLK1, 2, and 3. The inhibition of PLKs in nucleated cells induces apoptosis by perturbing the cell cycle with consequent engagement of mitotic catastrophe. BI2536 is being tested as chemotherapy in various phase I/II/III clinical trials. Erythrocytes do not have a nucleus; however, they may undergo programmed suicide with characteristic hallmarks including cell shrinkage and phosphatidylserine translocation to the cell surface. This particular death is baptized eryptosis. Our study explored whether BI2536 induces eryptosis. We used flow cytometry to access death in red blood cells. We analyzed the cellular volume, the intracellular calcium concentration, the cell surface phosphatidylserine exposure, and the ceramide abundance. In addition, we analyzed the effect of BI2536 on hemolysis. Our investigation showed that after 48 h of incubation with PLK inhibitor BI2536, erythrocytes lost volume and were positive for annexin­V without any effect on hemolysis. Cells also showed an abundance of ceramide and an increase of intracellular calcium. All these finding suggest that BI2536 provokes eryptosis in red blood cells, ostensibly in part due to Ca2+ entry and ceramide accumulation.

Investigation of the Renal Protective Effect of Combined Dietary Polyphenols in Streptozotocin-Induced Diabetic Aged Rats.

Natural polyphenols are widely reported to have a large range of pharmacological properties, especially antioxidant activities and free radical scavenging capacities. In this study, we investigate the effects of naringin, chlorogenic acid, and quercetin mixtures (NCQ) on renal fibrosis in streptozotocin (STZ)-induced diabetic aged rats and its underlying mechanisms for ten consecutive weeks. The oxidative defense system in the kidneys of treated rats was found to be improved. Several biomarkers were investigated including the blood urea nitrogen, creatinine, and uric acid. Moreover, antioxidant parameters were evaluated and we found that superoxide dismutase, catalase, glutathione peroxidase, Na+-K+-ATPase activities, the nitric oxide production, the protein carbonyl, the advanced oxidation protein products, lipid peroxidation, and reduced glutathione levels were all significantly balanced and close to control values. In addition, NCQ restored renal injuries and fibrosis as assessed by histological method and molecular biology investigation of the matrix metalloproteinase, the transforming growth factor-beta TGF-ß, the tumor necrosis factor TNFα, and p53 expression. Our study proposes the NCQ combination as potential plant-derived bioactive compounds to prevent diabetic nephropathy.

[Subungual exoxtosis: case report and literature review]. / Exostose sous-unguéale: à propos d'un cas et revue de la littérature.

Subungual exostosis is a benign, uncommon osteocartilaginous tumour that tends to recur. We here report the case of a 17-year boy with subungual exostosis, who reported a history of trauma. Treatment was based on direct surgery. The tumor was completely excised. The postoperative course was uneventful, with no recurrence identified.

[Acute osteomyelitis caused by community-acquired methicillin-resistant Staphylococcus aureus in children: about 15 cases]. / L´ostéomyélite aiguë à Staphylocoque aureus résistant à la méthicilline d´origine communautaire chez l´enfant: à propos de 15 cas.

The treatment of acute osteomyelitis is becoming more challenging since the emergence of community-acquired methicillin-resistant Staphylococcus aureus. We collected data on all patients with acute osteomyelitis caused by this germ over a period of 21 years (January 1995-December 2016) and we analyzed the peculiarities of this disorder. Our case series includes 15 children, with an average age of 9 years. All patients had affected lower limb. Local trauma was reported in 8 cases and skin carriage in 4 cases. Acute onset was reported in 12 cases associated with pseudo-paralysis of the affected limb. One patient had Staphylococcus aureus pulmonary infection with signs of septicopyemia. Blood culture was positive in 8 cases. In one case PCR assay for detection of Panton-Valentine leukocidin was performed with positive result. All these patients underwent surgical debridement and received secondarily adapted empirical antibiotic therapy. Outcome was good in 8 cases and poor in the other cases, with transition to a chronic state in 6 cases and one case of death. Pathological fracture was reported in 3 cases. Osteomyelitis cause by community-acquired methicillin-resistant Staphylococcus aureus is associated with a pejorative outcome. Recognizing the clinical and paraclinical signs of these infections is essential for a specific and early therapeutic management.

Novel Cyclophilin Inhibitor Decreases Cell Proliferation and Tumor Growth in Models of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient's life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel cyclophilin inhibitor, NV651, was able to significantly decrease proliferation in a diverse set of HCC cell lines. The exposure of HCC cells to NV651 caused an accumulation of cells during mitosis and consequent accumulation in the G2/M phase of the cell cycle. NV651 reduced tumor growth in vivo using an HCC xenograft model without affecting the body weights of the animals. The safety aspects of NV651 were also confirmed in primary human hepatocytes without any cytotoxic effects. Based on the results obtained in this study, we propose NV651 as a potential treatment strategy for HCC.

Gene Expression Signature of Acquired Chemoresistance in Neuroblastoma Cells.

Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. Patients with relapsed disease have a poor prognosis despite intense treatment. In the present study, we aimed to identify chemoresistance gene expression signatures in vincristine resistant neuroblastoma cells. We found that vincristine-resistant neuroblastoma cells formed larger clones and survived under reduced serum conditions as compared with non-resistant parental cells. To identify the possible mechanisms underlying vincristine resistance in neuroblastoma cells, we investigated the expression profiles of genes known to be involved in cancer drug resistance. This specific gene expression patterns could predict the behavior of a tumor in response to chemotherapy and for predicting the prognosis of high-risk neuroblastoma patients. Our signature could help chemoresistant neuroblastoma patients in avoiding useless and harmful chemotherapy cycles.

Discovery of epi-Enprioline as a Novel Drug for the Treatment of Vincristine Resistant Neuroblastoma.

Neuroblastoma is a childhood solid tumour originating from undifferentiated neural progenitor cells of the sympathetic nervous system. Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. In the present study, we aimed to identify novel drugs that can inhibit the growth and survival of chemoresistant neuroblastoma. High-throughput screening identified a small molecule, epi-enprioline that was able to induce apoptosis of vincristine-resistant neuroblastoma cells via the mitochondrial apoptotic pathway. Epi-enprioline reduced tumour growth in multiple preclinical models, including an orthotopic neuroblastoma patient-derived xenograft model in vivo. In summary, our data suggest that epi-enprioline can be considered as a lead compound for the treatment of vincristine-resistant neuroblastoma uncovering a novel strategy, which can be further explored as a treatment for drug-resistant neuroblastoma.

Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma.

Neuroblastoma is the most common paediatric cancer type. Patients diagnosed with high-risk neuroblastoma have poor prognosis and occasionally tumours relapse. As a result, novel treatment strategies are needed for relapse and refractory neuroblastoma patients. Here, we found that high expression of Mps1 kinase (mitotic kinase Monopolar Spindle 1) was associated with relapse-free neuroblastoma patient outcomes and poor overall survival. Silencing and inhibition of Mps1 in neuroblastoma or PDX-derived cells promoted cell apoptosis via the caspase-dependent mitochondrial apoptotic pathway. The mechanism of cell death upon Mps1 inhibition was dependent on the polyploidization/aneuploidization of the cells before undergoing mitotic catastrophe. Furthermore, tumour growth retardation was confirmed in a xenograft mouse model after Mps1-inhibitor treatment. Altogether, these results suggest that Mps1 expression and inhibition can be considered as a novel prognostic marker as well as a therapeutic strategy for the treatment of high-risk neuroblastoma patients.

The venoms of the lesser (Echiichthys vipera) and greater (Trachinus draco) weever fish- A review.

In comparison with other animal venoms, fish venoms remain relatively understudied. This is especially true for that of the lesser Echiichthys vipera and greater weever fish Trachinus draco which, apart from the isolation of their unique venom cytolysins, trachinine and dracotoxin, respectively, remain relatively uncharacterised. Envenomation reports mainly include mild symptoms consisting of nociception and inflammation. However, like most fish venoms, if the venom becomes systemic it causes cardiorespiratory and blood pressure changes. Although T. draco venom has not been studied since the 1990's, recent studies on E. vipera venom have discovered novel cytotoxic components on human cancer cells, but due to the scarcity of research on the molecular make-up of the venom, the molecule(s) causing this cytotoxicity remains unknown. This review analyses past studies on E. vipera and T. draco venom, the methods used in the , the venom constituents characterised, the reported symptoms of envenomation and compares these findings with those from other venomous Scorpaeniformes.

Preferential Killing of Tetraploid Colon Cancer Cells by Targeting the Mitotic Kinase PLK1.

BACKGROUND/AIMS: Chromosomal instability is a well-known factor in the progression of different types of cancer, including colorectal cancer. Chromosomal instability results in severely rearranged karyotypes and aneuploidy. Tetraploidy constitutes an intermediate phase during the polyploidy/aneuploidy cascade in oncogenesis, and tetraploid cells are particularly resistant to chemotherapy. Whether inhibition of the mitotic protein polo-like kinase 1 (PLK1) prevents the survival of tetraploid colon cancer cells is unknown. METHODS: Diploid and tetraploid cells were transfected with siPLK1 or treated with PLK1 inhibitor Bi2536 in combination with spindle poison. Cell toxicity was assessed via crystal violet staining and clonogenic assay. Flow cytometry assessment analyzed numerous cell apoptotic parameters and cell cycle phases. Synergistic activity between Bi2536 and paclitaxel, vincristine or colchicine was calculated using the CompuSyn software. RESULTS: Inhibition or abrogation of PLK1 prevented the survival of colon cancer cells, specifically tetraploid cells. The cell death induced by PLK inhibition was due to mitotic slippage, followed by the activation of the intrinsic pathway of apoptosis. We further demonstrated that co-treatment of the tetraploid colon cancer cells with a PLK1 inhibitor and the microtubule polymerisation inhibitor vincristine or colchicine, but not the microtubule depolymerisation inhibitor paclitaxel, provoked a lethal synergistic effect. CONCLUSION: PLK1 inhibition together with microtubule-targeting chemicals, serve as a potent therapeutic strategy for targeting tetraploid cancer cells.

Apatite calcific periarthritis of the radial collateral ligament of the thumb: a case report and review of the literature.

Calcification of the lateral collateral ligament of the metacarpophalangeal thumb is a rare pathology. It's may be due to a deposit of hydroxyapatite crystals. We report the case of a 36-year-old man with chronic pain of MCPP. X-ray and Ultrasound finds a calcium deposit of LCL.

[Post-traumatic carpo-metacarpal arthrosis of the fifth finger treated with stabilized arthroplasty: about two cases and literature review]. / Arthrose post-traumatique carpo-métacarpienne du cinquième doigt traitée par arthroplastie stabilisée: à propos de deux cas et revue de la littérature.

Old fractures and dislocations of the base of the fifth metacarpal may result in post-traumatic arthrosis which is troublesome from a functional point of view and characterized by a difficult management. Stabilized arthroplasty is based on arthroplastic resection of the base of the fifth metacarpal associated with lateral diaphysometaphyseal arthrodesis between the fourth and the fifth metacarpal. This study involving two patients aimed to describe the advantages and the peculiarities of stabilized arthroplasty compared to other techniques in the treatment of the sequelae of fractures and dislocations of the base of the fifth metacarpal.

[Tuberculous bursitis of the shoulder in a patient with chronic renal insufficiency: about a case]. / Bursite tuberculeuse de l'épaule chez une insuffisante rénale chronique: à propos d'un cas.

Tuberculosis of the shoulder is rare. It encompasses all articular and periarticular tuberculouses of the shoulder. Its insidious evolution, mimicking inflammatory and degenerative diseases, reflects the frequency of its diagnostic delay. We report a rare case of tuberculous bursitis of the shoulder in a woman living in rural areas, with renal insufficiency and treated for peritoneal TB and psoas. The anamnesis revealed signs of tuberculous impregnation. Clinical examination showed painful swelling of the shoulder associated with stiffness. MRI of the shoulder objectified infectious bursal disease. Its tuberculous origin was confirmed by the histological examination of ultrasound-guided synovial biopsy. The patient underwent TB treatment with good outcome. At 9-year follow-up, the patient had satisfactory articular function with no recurrence of infectious disease.

Spontaneous and simultaneous complete bilateral rupture of the quadriceps tendon in a patient receiving hemodialysis: A case report and literature review.

The spontaneous and simultaneous rupture of both quadriceps tendons is uncommon and has rarely been reported in the literature. The current case involves a 43-year-old man with end-stage renal disease requiring hemodialysis for the past 20 years. The patient experienced bilateral knee pain and swelling and was unable to bear weight. Physical examination revealed bilateral quadriceps tendon defect above the patella and loss of active extension. Although plain radiographs of both knees showed no fracture or widening of the joint space, an inferiorly positioned patella was observed. Ultrasonography of the knees revealed a quadriceps tendon defect at the upper edge of each patella, while MR imaging revealed a tear in each quadriceps tendon from the superior poles of the patella. The patient then underwent surgical correction wherein the tendons were repaired using sutures passed through drill holes in the patella. The knees were immobilized with splints for 4 wk before starting physiotherapy. The patient subsequently regained full functional activity within 1 year.

In Silico Identification and in Vitro Analysis of B and T-Cell Epitopes of the Black Turtle Bean (Phaseolus Vulgaris L.) Lectin.

BACKGROUND/AIMS: The incidence of lectin allergic disease is increasing in recent decades, and definitive treatment is still lacking. Identification of B and T-cell epitopes of allergen will be useful in understanding the allergen antibody responses as well as aiding in the development of new diagnostics and therapy regimens for lectin poisoning. In the current study, we mainly addressed these questions. METHODS: Three-dimensional structure of the lectin from black turtle bean (Phaseolus vulgaris L.) was modeled using the structural template of Phytohemagglutinin from P. vulgaris (PHA-E, PDB ID: 3wcs.1.A) with high identity. The B and T-cell epitopes were screened and identified by immunoinformatics and subsequently validated by ELISA, lymphocyte proliferation and cytokine profile analyses. RESULTS: Seven potential B-cell epitopes (B1 to B7) were identified by sequence and structure based methods, while three T-cell epitopes (T1 to T3) were identified by the predictions of binding score and inhibitory concentration. The epitope peptides were synthesized. Significant IgE binding capability was found in B-cell epitopes (B2, B5, B6 and B7) and T2 (a cryptic B-cell epitope). T1 and T2 induced significant lymphoproliferation, and the release of IL-4 and IL-5 cytokine confirmed the validity of T-cell epitope prediction. Abundant hydrophobic amino acids were found in B-cell epitope and T-cell epitope regions by amino acid analysis. Positively charged amino acids, such as His residue, might be more favored for B-cell epitope. CONCLUSION: The present approach can be applied for the identification of epitopes in novel allergen proteins and thus for designing diagnostics and therapies in lectin allergy.