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1.
Rev Med Suisse ; 19(827): 994-997, 2023 May 17.
Artigo em Francês | MEDLINE | ID: mdl-37195117

RESUMO

The jumping finger is commonly found clinical finding in various pathologies. However, trigger finger is the main cause. Therefore, the general practitioner should be aware of the differential diagnoses of jumping finger and the multiple presentation of trigger finger. This article aim is to guide the general practitioner diagnose and cure trigger finger.


Le ressaut digital est un signe clinique présent dans de multiples pathologies. Le doigt à ressort en est de loin la cause la plus fréquente. Le médecin traitant ne doit pas ignorer les nombreuses pathologies pouvant mimer ce diagnostic et les multiples formes de doigt à ressort. Le but de cet article est d'orienter le médecin traitant dans sa conduite diagnostique et thérapeutique face à un ressaut digital.


Assuntos
Clínicos Gerais , Dedo em Gatilho , Humanos , Dedos , Conscientização , Diagnóstico Diferencial
2.
Rev Med Suisse ; 19(818): 526-529, 2023 Mar 15.
Artigo em Francês | MEDLINE | ID: mdl-36920011

RESUMO

Surgical treatment of hands in rheumatoid arthritis is adapted to functional and aesthetical needs of the patient. In dialogue between the patient, rheumatologist and general practitioner, the hand surgeon tailors the solution in each case. During last 20 years, the biological drugs have revolutionized the medical treatment, in parallel the hand surgery developed mostly in the domain of arthroplasty. This article reviews the therapeutic options a hand surgeon can offer his patients with inflammatory diseases with a focus on recent development.


La prise en charge chirurgicale des maladies rhumatismales au niveau de la main repose essentiellement sur les besoins fonctionnels et esthétiques du patient. L'enjeu du chirurgien de la main est de proposer une solution chirurgicale adaptée à chaque cas, après avoir effectué une concertation avec le patient, le rhumatologue et le médecin traitant. En discussion avec ces derniers, le chirurgien de la main peut proposer une solution chirurgicale adaptée à chaque cas. Si le traitement médical a révolutionné, aujourd'hui, la prise en charge des pathologies inflammatoires rhumatismales, l'éventail des options thérapeutiques chirurgicales a également évolué, notamment dans le domaine de l'arthroplastie, depuis une vingtaine d'années. Cet article propose un aperçu de ces options thérapeutiques chirurgicales.


Assuntos
Artrite Reumatoide , Mãos , Humanos , Mãos/cirurgia , Artroplastia , Artrite Reumatoide/cirurgia
3.
Microsurgery ; 42(3): 226-230, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34636060

RESUMO

BACKGROUND: Metacarpal nonunion is a rare condition. The osteogenic capacity of periosteal free flap was investigated in five patients with metacarpal nonunion and impaired bone vascularization. PATIENTS AND METHODS: Surgery was performed between 64 and 499 days after the initial bone osteosynthesis. The average age was 27.6 (range 16-32) years. Nonunion was caused by excessive periosteal removal in two patients, extensive open trauma in three. Four nonunions were diaphyseal, one metaphyseal. A periosteal medial femoral condyle free flap was raised on the descending genicular artery for four patients, the superomedial genicular artery for one. After osteosynthesis with a plate, the flap was wrapped around the metacarpal, overlapping the bone proximally and distally. The recipient vessel were the dorsal branch of the radial artery and a vena comitans in the anatomical snuffbox in four patients, at the base of the first webspace in one. RESULTS: The flap size ranged from 5 × 3.5 cm to 8 × 4 cm. No postoperative complication occurred. Radiological bone union was achieved 3 to 8 months after surgery. One patient had a full range of motion, one a slight extension lag of the proximal interphalangeal joint, two moderate joint stiffness of the proximal interphalangeal or metacarpophalangeal joint (one requiring plate removal and extensor tenolysis), one severe stiffness that allowed using a hook grip which was the aim of the surgery. CONCLUSION: In case of metacarpal nonunion with impaired bone vascularization, the periosteal medial femoral condyle free flap provides an effective and biomimetic approach to bone healing.


Assuntos
Fraturas não Consolidadas , Retalhos de Tecido Biológico , Ossos Metacarpais , Adolescente , Adulto , Fêmur/cirurgia , Fraturas não Consolidadas/diagnóstico por imagem , Fraturas não Consolidadas/cirurgia , Humanos , Ossos Metacarpais/cirurgia , Amplitude de Movimento Articular , Adulto Jovem
4.
Surg Radiol Anat ; 44(2): 201-205, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35024904

RESUMO

Ulnar/cubital tunnel syndrome is the second most common compressive neuropathy of the upper limb. Permanent location of the ulnar nerve anterior to the medial epicondyle is extremely rare, with only five cases reported in the literature. Using ultrasound elastography and diffusion tensor imaging with fiber tractography, we diagnosed a case in which ulnar nerve entrapment was associated with anterior nerve location. Surgical release confirmed the diagnosis and the patient was symptom free 3 months after surgery.


Assuntos
Síndrome do Túnel Ulnar , Técnicas de Imagem por Elasticidade , Síndromes de Compressão do Nervo Ulnar , Imagem de Tensor de Difusão , Humanos , Nervo Ulnar/diagnóstico por imagem , Síndromes de Compressão do Nervo Ulnar/diagnóstico por imagem
5.
AJR Am J Roentgenol ; 216(2): 349-354, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32822225

RESUMO

OBJECTIVE. The purpose of this study is to evaluate the potential benefit of spectral imaging, notably electron density imaging, in patients with suspected or confirmed coronavirus disease (COVID-19), by retrospectively reviewing the cases of four patients who each underwent two chest CT scans for confirmed COVID-19. CONCLUSION. The use of spectral CT with electron density imaging could improve the assessment of lung lesion extent in patients with early-stage COVID-19.


Assuntos
COVID-19/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
J Hand Surg Am ; 46(11): 1023.e1-1023.e7, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33865656

RESUMO

PURPOSE: The spiral oblique retinacular ligament (SORL) procedure acts as a dynamic tenodesis to restore distal interphalangeal joint (DIP) extension and restrain proximal interphalangeal hyperextension. Despite the ingenious technique based on the oblique retinacular ligament anatomy, obtaining strong internal fixation remains an issue during the SORL procedure. We present a modified technique using the flexor digitorum profundus (FDP) hemi-tendon transfer. METHODS: We dissected 5 fresh cadaveric specimens to evaluate morphometric parameters of the SORL procedure using the hemi-FDP. The volar groove of the FDP tendon was identified in zone I of the flexor sheath and the tendon was divided into radial and ulnar bundles. The selected hemi-tendon was divided at the proximal edge of the A1 pulley and a SORL procedure was performed through a transosseous tunnel in the distal phalanx. This technique was used in 3 patients with swan neck deformity. RESULTS: The optimal distance between the DIP joint and the anterior drill hole of the transosseous tunnel was 7.6 mm (range, 6.8-8.5 mm). The relative loss of length of the tendon owing to the SORL path was 25.8 mm (range, 19.6-29.9 mm). In the clinical cases, the procedure improved DIP joint extension lag and prevented proximal interphalangeal joint hyperextension. Preserving one-half of the FDP allowed complete flexion of the DIP joint. CONCLUSIONS: The procedure is technically feasible. Its main advantages are that a distal suture is not required and that the substantial length of the tendon allows sturdy proximal internal fixation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.


Assuntos
Deformidades Adquiridas da Mão , Transferência Tendinosa , Articulações dos Dedos/cirurgia , Humanos , Ligamentos , Tendões/cirurgia
8.
Surg Radiol Anat ; 43(5): 721-726, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33398519

RESUMO

PURPOSE: The flexor carpi radialis brevis (FCRB) is a supernumerary musculotendinous structure of the wrist that has been the focus of some interest in the last decade. While its anatomy is well known, its in vivo function remains unknown as it has never been studied. METHODS: Eleven cases of FCRB underwent a multimodal ultrasound consisting of B-mode, color Doppler and shear wave elastography. RESULTS: A pennate shape was observed in all cases and the mean value of the cross-sectional area was 0.8 cm2 (SD 0.3 cm2). Young's modulus was significantly (p < 0.01) different between the resting position and active flexion or passive extension. CONCLUSION: Our study demonstrates that the FCRB shows biomechanics of a typical skeletal muscle and is voluntarily controlled by flexing the wrist. Absent in other vertebrate taxa, the FCRB probably plays a role in active stability of the wrist in Human.


Assuntos
Variação Anatômica , Antebraço/anormalidades , Músculo Esquelético/anormalidades , Punho/anormalidades , Adulto , Fenômenos Biomecânicos , Técnicas de Imagem por Elasticidade , Feminino , Antebraço/diagnóstico por imagem , Antebraço/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Ultrassonografia Doppler em Cores , Punho/diagnóstico por imagem , Punho/fisiopatologia , Adulto Jovem
9.
Curr Opin Oncol ; 31(2): 100-107, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30562314

RESUMO

PURPOSE OF REVIEW: Although extensively studied for over a decade, gene expression programs established at the epigenetic and/or transcriptional levels do not fully characterize cancer stem cells (CSC). This review will highlight the latest advances regarding the functional relevance of different key post-transcriptional regulations and how they are coordinated to control CSC homeostasis. RECENT FINDINGS: In the past 2 years, several groups have identified master post-transcriptional regulators of CSC genetic programs, including RNA modifications, RNA-binding proteins, microRNAs and long noncoding RNAs. Of particular interest, these studies reveal that different post-transcriptional mechanisms are coordinated to control key signalling pathways and transcription factors to either support or suppress CSC homeostasis. SUMMARY: Deciphering molecular mechanisms coordinating plasticity, survival and tumourigenic capacities of CSCs in adult and paediatric cancers is essential to design new antitumour therapies. An entire field of research focusing on post-transcriptional gene expression regulation is currently emerging and will significantly improve our understanding of the complexity of the molecular circuitries driving CSC behaviours and of druggable CSC weaknesses.


Assuntos
Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Processamento Pós-Transcricional do RNA , Animais , Homeostase , Humanos , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo
10.
Microsurgery ; 39(5): 405-415, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30672005

RESUMO

BACKGROUND: We evaluated composite anterolateral thigh (ALT) flaps including vascularized fascia lata (FL), for stable soft tissue coverage and tendons restoration at various joint levels in a one-stage procedure. METHODS: We performed a retrospective investigation including 21 "functional" ALT flaps between November 2006 and December 2016. In all patients included, FL was shaped to anatomical reproduce a tendon structure. Functional analysis included range of motion and force assessment. Functional scores were established according to Chen classification, DASH, and LEFS score. Defects resulted from tumor excision, trauma, burn, or infection-debridement and were distributed in four main anatomical districts: knee (seven cases), ankle (six cases), forearm-elbow (four cases), and hand-wrist level (three cases). RESULTS: Nineteen flaps were raised as free flaps, while two as distally-based propeller flaps. Average follow-up was 38 months. Major complication requiring the harvest of a second flap was seen in two patients, whereas three flaps presented superficial necrosis and was treated in an outpatient regimen. We observed 81% of total ROM recovery compared to contralateral sides with 89% recovered articular stability. Best articulation outcomes were present in elbow reconstruction, while ankle reconstructions showed less articularity. Hospital stay was significantly reduced in hand and wrist functional reconstruction when compared with reconstruction at the ankle level (P < 0.05). CONCLUSION: The ALT flap extended to vascularized FL provides a particularly effective and resistant tissue that can be folded to reconstruct and support tendinous structures. This can restore functional and structural integrity after complex defects in a single stage procedure.


Assuntos
Fascia Lata/transplante , Retalho Miocutâneo/transplante , Procedimentos de Cirurgia Plástica/métodos , Lesões dos Tecidos Moles/cirurgia , Cicatrização/fisiologia , Adulto , Traumatismos do Tornozelo/diagnóstico , Traumatismos do Tornozelo/cirurgia , Estudos de Coortes , Fascia Lata/cirurgia , Feminino , Sobrevivência de Enxerto/fisiologia , Hospitais Universitários , Humanos , Escala de Gravidade do Ferimento , Traumatismos do Joelho/diagnóstico , Traumatismos do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Retalho Miocutâneo/irrigação sanguínea , Prognóstico , Amplitude de Movimento Articular/fisiologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Lesões dos Tecidos Moles/diagnóstico , Suíça , Transferência Tendinosa/métodos , Coxa da Perna/cirurgia , Coleta de Tecidos e Órgãos/métodos , Traumatismos do Punho/diagnóstico , Traumatismos do Punho/cirurgia , Adulto Jovem
11.
RNA ; 21(5): 887-97, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25805855

RESUMO

The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3' UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3' UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3' UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3' UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMD-inhibiting cis elements in the first 200 nt. A smaller subset of long 3' UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3' UTRs.


Assuntos
Regiões 3' não Traduzidas/genética , Degradação do RNAm Mediada por Códon sem Sentido/genética , Elementos Reguladores de Transcrição/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Bases , Células HeLa , Humanos , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Polirribossomos/metabolismo , RNA Helicases , Transativadores/genética , Transativadores/metabolismo
13.
Int J Mol Sci ; 18(5)2017 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-28505080

RESUMO

Fingertip response to trauma represents a fascinating example of tissue regeneration. Regeneration derives from proliferative mesenchymal cells (blastema) that subsequently differentiate into soft and skeletal tissues. Clinically, conservative treatment of the amputated fingertip under occlusive dressing can shift the response to tissue loss from a wound repair process towards regeneration. When analyzing by Immunoassay the wound exudate from occlusive dressings, the concentrations of brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were higher in fingertip exudates than in burn wounds (used as controls for wound repair versus regeneration). Vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor (PDGF) were highly expressed in both samples in comparable levels. In our study, pro-inflammatory cytokines were relatively higher expressed in regenerative fingertips than in the burn wound exudates while chemokines were present in lower levels. Functional, vascular and mechanical properties of the regenerated fingertips were analyzed three months after trauma and the data were compared to the corresponding fingertip on the collateral uninjured side. While sensory recovery and morphology (pulp thickness and texture) were similar to uninjured sides, mechanical parameters (elasticity, vascularization) were increased in the regenerated fingertips. Further studies should be done to clarify the importance of inflammatory cells, immunity and growth factors in determining the outcome of the regenerative process and its influence on the clinical outcome.


Assuntos
Queimaduras/genética , Diferenciação Celular/genética , Traumatismos dos Dedos/genética , Regeneração/genética , Adulto , Idoso , Fator Neurotrófico Derivado do Encéfalo/genética , Queimaduras/fisiopatologia , Exsudatos e Transudatos/imunologia , Exsudatos e Transudatos/metabolismo , Exsudatos e Transudatos/fisiologia , Traumatismos dos Dedos/fisiopatologia , Humanos , Fator Inibidor de Leucemia/genética , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Curativos Oclusivos , Fator de Crescimento Derivado de Plaquetas/genética , Fator A de Crescimento do Endotélio Vascular/genética , Cicatrização/genética , Cicatrização/fisiologia
15.
Eur Radiol ; 24(12): 3003-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25173625

RESUMO

PURPOSE: To evaluate noise level and contrast-to-noise ratio (CNR) with various kVp-mAs pairs producing the same computed tomography dose index (CTDI) value. The 80 kVp and new 70-kVp settings were compared. MATERIALS AND METHODS: The noise was measured in 10 ovoid water phantoms with different diameters from 10 cm to 28 cm. Contrast was obtained from CTs of iodine-filled tubes. Spiral acquisition protocols at 70 kVp and 80 kVp, with the same CTDI, were applied. In the clinical study, two matched groups, each of 21 paediatric patients, underwent 70-kVp or 80-kVp ECG-gated iodinated-enhanced sequential CT. RESULTS: Noise was significantly higher with 70 kVp than 80-kVp settings for all phantom sizes. Estimated CNR with phantoms was higher at 70 kVp than 80 kVp, and the difference decreased from 17% to 3% as phantom size increased. The mean CNR in paediatric patients was 15.2 at 70 kVp and 14.3 at 80 kVp (ns). The CNR difference was significantly larger in the small-child subgroup. CONCLUSION: Noise level is slightly higher at the 70-kVp than the 80-kVp setting, but the CNR is higher, particularly for small children. Therefore, 70 kVp may be appropriate for contrast-enhanced CT examinations and 80 kVp for non-enhanced CT in small children. KEY POINTS: 70-kVp settings provide a slightly higher noise level compared to 80-kVp settings. The CNR is higher with 70-kVp than with 80-kVp settings. Without contrast, 80-kVp settings may be preferable over 70-kVp settings.


Assuntos
Cardiopatias Congênitas/diagnóstico por imagem , Razão Sinal-Ruído , Tomografia Computadorizada por Raios X/normas , Criança , Pré-Escolar , Meios de Contraste , Humanos , Lactente , Recém-Nascido , Iodo , Imagens de Fantasmas , Doses de Radiação , Tomografia Computadorizada por Raios X/métodos
16.
Hand Surg Rehabil ; 43(2): 101636, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38215880

RESUMO

Ultrasound elastography is a recently developed method for accurate measurement of soft tissue stiffness in addition to the clinician's subjective evaluation. The present review briefly describes the ultrasound elastography techniques and outlines clinical applications for tendon, muscle, nerve, skin and other soft tissues of the hand and upper limb. Strain elastography provides a qualitative evaluation of the stiffness, and shear-wave elastography generates quantitative elastograms superimposed on a B-mode image. The stiffness in degenerative tendinopathy and/or tendon injury was significantly lower than in a normal tendon in several studies. Elastography is also a reliable method to evaluate functional muscle activity, compared to conventional surface electromyography. The median nerve is consistently stiffer in patients with carpal tunnel syndrome than in healthy subjects, on whatever ultrasound elastography technique. Elastography distinguishes normal skin from scars and can be used to evaluate scar severity and treatment. Elastography has huge clinical applications in musculoskeletal tissues. Continued development of systems and increased training of clinicians will expand our knowledge of elastography and its clinical applications in the future.


Assuntos
Técnicas de Imagem por Elasticidade , Humanos , Extremidade Superior/diagnóstico por imagem , Extremidade Superior/fisiopatologia , Mãos/diagnóstico por imagem , Mãos/fisiopatologia , Síndrome do Túnel Carpal/diagnóstico por imagem , Síndrome do Túnel Carpal/fisiopatologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Tendões/diagnóstico por imagem , Traumatismos dos Tendões/diagnóstico por imagem , Traumatismos dos Tendões/fisiopatologia , Cicatriz/diagnóstico por imagem , Cicatriz/fisiopatologia
17.
Ann Plast Surg ; 71(5): 595-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23187714

RESUMO

Soft-tissue defects of the distal third of the leg are common occurrences in trauma centers. The authors present the anatomic basis and their clinical experience using the flexor digitorum longus muscle flap. Ten cadaver specimens were dissected to evaluate the potential use of this flap for soft-tissue coverage in the lower third of the leg. Eleven patients underwent a soft-tissue reconstruction in the distal third of the leg with this flap. The average size of the defect covered by this flap was 11.3 cm. This transfer flap was used in 7 cases exclusively or in combination in 4 cases. No functional deficit and good plastic result were observed in all cases. Ease of elevation and reliability has made this transfer flap the procedure of choice for small soft-tissue defects over the proximal portion of the distal tibia in our institution.


Assuntos
Retalhos de Tecido Biológico , Perna (Membro)/cirurgia , Músculo Esquelético/transplante , Procedimentos de Cirurgia Plástica/métodos , Lesões dos Tecidos Moles/cirurgia , Cadáver , Humanos
18.
J Clin Med ; 13(1)2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38202053

RESUMO

BACKGROUND: The original description of boxer's knuckle injury of the fifth ray mentions that the injury occurs between the extensor digitorum communis (EDC) and the extensor digiti minimi (EDM). Subsequent reports claim similar findings. Anatomical studies show that the EDC of the fifth ray is absent in most patients, while the EDM is generally composed of two slips. We present a modification of the current description of boxer's knuckle injury of the little finger based on the correlation between advanced preoperative 3D imaging and intraoperative findings. METHODS: Five patients were investigated preoperatively using high-resolution ultrasound and 3D tendon reconstruction-based MR arthrography. Surgical exploration identified the lesion site relative to the EDM and EDC. RESULTS: All patients had two slips of the EDM and no EDC to the fifth ray. The injury appeared as a longitudinal tear of the EDM between its two slips. The mean gap was 7.8 mm (range 4.5-10 mm) on the pathological side vs. 1.3 mm (range 1-2 mm) on the healthy contralateral side. CONCLUSIONS: We believe that previous descriptions of boxer's knuckle of the fifth ray are inaccurate. High-resolution ultrasound and 3D reconstructions based on MR arthrography are reliable diagnostic tools allowing to locate the injury with precision.

19.
Mol Oncol ; 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37452637

RESUMO

Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells.

20.
Nat Commun ; 14(1): 356, 2023 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690642

RESUMO

Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells. RSL24D1 is associated with nuclear pre-ribosomes and is required for the biogenesis of 60S subunits in mouse ESCs. Interestingly, RSL24D1 depletion significantly impairs global translation, particularly of key pluripotency factors and of components from the Polycomb Repressive Complex 2 (PRC2). While having a moderate impact on differentiation, RSL24D1 depletion significantly alters ESC self-renewal and lineage commitment choices. Altogether, these results demonstrate that RSL24D1-dependant ribosome biogenesis is both required to sustain the expression of pluripotent transcriptional programs and to silence PRC2-regulated developmental programs, which concertedly dictate ESC homeostasis.


Assuntos
Células-Tronco Embrionárias , Células-Tronco Pluripotentes , Humanos , Animais , Camundongos , Células-Tronco Embrionárias/metabolismo , Diferenciação Celular/genética , Complexo Repressor Polycomb 2/metabolismo
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