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1.
J Hand Surg Am ; 48(8): 822-826, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37191604

RESUMO

The symptoms of amyotrophic lateral sclerosis (ALS) can mimic those of compressive neuropathies, such as carpal and cubital tunnel syndromes, especially early in a patient's clinical course. We surveyed members of the American Society for Surgery of the Hand and found that 11% of active and retired members have performed nerve decompression surgeries on patients later diagnosed with ALS. Hand surgeons are commonly the first providers to evaluate patients with undiagnosed ALS. As such, it is important to be aware of the history, signs, and symptoms of ALS to provide an accurate diagnosis and prevent unnecessary morbidities, such as nerve decompression surgery, which invariably results in poor outcomes. The major "red flag" symptoms warranting further work-up include weakness without sensory symptoms, profound weakness and atrophy in multiple nerve distributions, progressively bilateral and global symptoms, presence of bulbar symptoms (such as tongue fasciculations and speech/swallowing difficulties), and, if surgery is performed, failure to improve. If any of these red flags are present, we recommend neurodiagnostic testing and prompt referral to a neurologist for further work-up and treatment.


Assuntos
Esclerose Lateral Amiotrófica , Síndrome do Túnel Ulnar , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/cirurgia , Encaminhamento e Consulta , Erros de Diagnóstico , Procedimentos Neurocirúrgicos
2.
Br J Cancer ; 122(4): 539-544, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31806878

RESUMO

BACKGROUND: Fulfilling the promise of cancer immunotherapy requires novel predictive biomarkers to characterise the host immune microenvironment. Deciphering the complexity of immune cell interactions requires an automated multiplex approach to histological analysis of tumour sections. We tested a new automatic approach to select tissue and quantify the frequencies of cell-cell spatial interactions occurring in the PD1/PD-L1 pathway, hypothesised to reflect immune escape in oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Single sections of diagnostic biopsies from 72 OPSCC patients were stained using multiplex immunofluorescence (CD8, PD1, PD-L1, CD68). Following multispectral scanning and automated regions-of-interest selection, the Hypothesised Interaction Distribution (HID) method quantified spatial proximity between cells. Method applicability was tested by investigating the prognostic significance of co-localised cells (within 30 µm) in patients stratified by HPV status. RESULTS: High frequencies of proximal CD8+ and PD-L1+ (HR 2.95, p = 0.025) and PD1+ and PD-L1+ (HR 2.64, p = 0.042) cells were prognostic for poor overall survival in patients with HPV negative OPSCC (n = 31). CONCLUSION: The HID method can quantify spatial interactions considered to reflect immune escape and generate prognostic information in OPSCC. The new automated approach is ready to test in additional cohorts and its applicability should be explored in research and clinical studies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Orofaríngeas/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Aprendizado Profundo , Humanos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Orofaríngeas/mortalidade , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
3.
Ann Allergy Asthma Immunol ; 125(1): 17-27, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044451

RESUMO

OBJECTIVE: The goal of a vaccine is to prime the immune response so the immune memory can facilitate a rapid response to adequately control the pathogen on natural infection and prevent disease manifestation. This article reviews the main elements that provide for the development of safe and effective vaccines. DATA SOURCES: Literature covering target pathogen epidemiology, the key aspects of the functioning immune response underwriting target antigen selection, optimal vaccine formulation, preclinical and clinical trial studies necessary to deliver safe and efficacious immunization. STUDY SELECTIONS: Whole live, inactivated, attenuated, or partial fractionated organism-based vaccines are discussed in respect of the balance of reactogenicity and immunogenicity. The use of adjuvants to compensate for reduced immunogenicity is described. The requirements from preclinical studies, including establishing a proof of principle in animal models, the design of clinical trials with healthy volunteers that lead to licensure and beyond are reviewed. RESULTS: The 3 vaccine development phases, preclinical, clinical, and post-licensure, integrate the requirements to ensure safety, immunogenicity, and efficacy in the final licensed product. Continuing monitoring of efficacy and safety in the immunized populations is essential to sustain confidence in vaccination programs. CONCLUSION: In an era of increasing vaccine hesitancy, the need for a better and widespread understanding of how immunization acts to counteract the continuing and changing risks from the pathogenic world is required. This demands a societal responsibility for obligate education on the benefits of vaccination, which as a medical intervention has saved more lives than any other procedure.


Assuntos
Vacinação , Vacinas , Animais , Humanos
4.
Instr Course Lect ; 69: 331-346, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017736

RESUMO

This chapter will explore scapholunate ligament injuries with a focus on injury recognition, diagnosis, the natural history, and options for treatment. Treatment is based upon injury factors, patient factors, and surgeon preference. The classification systems in common use will be discussed, and treatment options will be explored, including nonsurgical, arthroscopic, repair, reconstruction, pain relieving measures, and salvage procedures.


Assuntos
Artrite , Osso Semilunar , Osso Escafoide , Traumatismos do Punho , Humanos , Ligamentos Articulares
5.
J Hand Surg Am ; 45(6): 503-511, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32229054

RESUMO

PURPOSE: Injectable drug use (IDU) is a national epidemic, public health problem, and common cause of hand and upper extremity (UE) infections. This study assesses the epidemiology of the IDU patient population presenting to a Midwestern academic medical center emergency department (ED) and examines predictors influencing morbidity and outcomes. METHODS: A retrospective review was performed using International Classification of Diseases, Ninth Revision (ICD-9) codes to identify all adult patients presenting to the ED with hand/UE infections, with and without concurrent IDU diagnoses, over a period of 2.5 years. Demographics and clinical factors were examined utilizing bivariate and multivariable analyses to identify predictors of outcomes, including not completing outpatient follow-up and leaving against medical advice (AMA). RESULTS: A total of 1,482 patients with 1,754 ED visits for hand/UE infections were identified, including 308 patients with IDU-acquired infections (396 visits) and 1,174 patients with non-IDU infections (1,358 visits). Psychiatric comorbidities and hepatitis C were common in the IDU group (51% and 39%, respectively), and 31% of IDU patients were uninsured. Heroin use was identified in 96% of visits. The IDU infections were more likely to have surgical intervention than those in non-IDU patients (16% vs 6%), and a longer mean length hospital stay (2.4 vs 0.9 days). The IDU patients were more likely than non-IDU patients to leave AMA. In multivariable analysis, IDU, psychiatric comorbidity, and insurance status were independent predictors (P < .05) for leaving AMA. CONCLUSIONS: In the setting of a national epidemic, hand/UE infections due to IDU are a common problem seen by hand surgeons. This study characterizes the growing IDU patient population at an urban academic medical center, examining the largest cohort of these patients to date. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.


Assuntos
Usuários de Drogas , Abuso de Substâncias por Via Intravenosa , Adulto , Serviço Hospitalar de Emergência , Humanos , Estudos Retrospectivos , Abuso de Substâncias por Via Intravenosa/epidemiologia , Extremidade Superior
6.
J Hand Surg Am ; 45(4): 360.e1-360.e4, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31653469

RESUMO

PURPOSE: To describe the branching pattern of the posterior antebrachial cutaneous nerve (PABCN) and to corroborate measurements and observations reported by previous authors. METHODS: Using 28 fresh-frozen cadaver specimens, we dissected the PABCN from its origin from the radial nerve to its terminal arborization in the distal forearm. Measurements relative to the lateral humeral epicondyle were recorded. The course of the nerve over the muscles of the mobile wad and its branching pattern in the proximal forearm were noted. RESULTS: The PABCN originated from the radial nerve at a mean of 14.2 cm proximal to the lateral epicondyle. The fascial hiatus through which the PABCN emerged to become superficial was a mean of 8.2 cm proximal to the lateral epicondyle. All specimens had at least 1 longitudinal branch that passed a mean of 2.8 cm anterior to the lateral epicondyle. Thirty-two percent of specimens had a lesser proximal branch in the distal third of the lateral arm; 86% had an epicondylar branch to the lateral epicondyle; and 21% had a second longitudinal branch. Ninety-three percent had a longitudinal branch coursing over the interval between the brachioradialis and the extensor carpi radialis longus in the proximal forearm. CONCLUSIONS: After becoming superficial in the distal brachium, the PABCN typically gives off a discrete epicondylar branch and then continues distally in the forearm as 1 or 2 longitudinal branches. In addition, in the proximal third of the forearm, a consistent longitudinal branch of the PABCN courses over the interval between the brachioradialis and the extensor carpi radialis longus. This review confirms previous observations of the PABCN. CLINICAL RELEVANCE: Knowledge of the course of the PABCN will assist surgeons in identifying and avoiding injury in clinical situations such as plating the proximal radius or releasing the radial tunnel.


Assuntos
Antebraço , Nervo Radial , Braço , Cadáver , Cotovelo , Humanos , Nervo Radial/anatomia & histologia , Ulna
7.
J Hand Surg Am ; 43(10): 927-931, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29573894

RESUMO

PURPOSE: Most distal radius (DR) fractures are initially managed with closed reduction and orthosis application. Mini-C-arm fluoroscopy provides assessment of reduction quality in real time. Our null hypothesis was that there would be no difference in the reduction quality of DR fractures in the emergency department when using mini-C-arm fluoroscopy during reduction compared with standard reduction techniques (evaluating reduction quality with orthogonal radiographs taken in an orthosis). METHODS: Sixty-three consecutive patients with closed DR fractures requiring reduction between April 2015 and April 2017 were prospectively randomized to standard versus fluoroscopically aided reductions. Reductions were performed by orthopedic surgery residents. The primary outcome measurement was reduction quality (radial height, radial inclination, ulnar variance, and volar tilt) as measured on postreduction radiographs. RESULTS: Standard reductions were performed in 34 patients and fluoroscopically aided reductions in 29 patients. The 2 groups were similar in regards to all potential confounders that were analyzed. No differences in postreduction radial height, radial inclination, ulnar variance, or volar tilt were noted. Overall reduction attempts and subjective difficulty of fracture reduction were increased when using fluoroscopy. The rate of initial operative management did not differ between groups. CONCLUSIONS: The use of mini-C-arm fluoroscopy during the initial closed reduction of adult DR fractures results in equivalent postreduction radiographic parameters when compared with conventional reduction techniques. Additional research regarding time spent in the emergency department and overall cost could elucidate potential benefits of fluoroscopically aided DR fracture reduction. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.


Assuntos
Redução Fechada , Fluoroscopia , Fraturas Fechadas/diagnóstico por imagem , Fraturas Fechadas/terapia , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Feminino , Humanos , Internato e Residência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
J Neurosci ; 36(31): 8210-27, 2016 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-27488640

RESUMO

UNLABELLED: Neural circuits that undergo reorganization by newborn interneurons in the olfactory bulb (OB) are necessary for odor detection and discrimination, olfactory memory, and innate olfactory responses, including predator avoidance and sexual behaviors. The OB possesses many interneurons, including various types of granule cells (GCs); however, the contribution that each type of interneuron makes to olfactory behavioral control remains unknown. Here, we investigated the in vivo functional role of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic arborization of 5T4-expressing GCs (5T4 GCs), the level of which is reduced in the OB of 5T4 knock-out (KO) mice. Electrophysiological recordings with acute OB slices indicated that external tufted cells (ETCs) can be divided into two types, bursting and nonbursting. Optogenetic stimulation of 5T4 GCs revealed their connection to both bursting and nonbursting ETCs, as well as to mitral cells (MCs). Interestingly, nonbursting ETCs received fewer inhibitory inputs from GCs in 5T4 KO mice than from those in wild-type (WT) mice, whereas bursting ETCs and MCs received similar inputs in both mice. Furthermore, 5T4 GCs received significantly fewer excitatory inputs in 5T4 KO mice. Remarkably, in olfactory behavior tests, 5T4 KO mice had higher odor detection thresholds than the WT, as well as defects in odor discrimination learning. Therefore, the loss of 5T4 attenuates inhibitory inputs from 5T4 GCs to nonbursting ETCs and excitatory inputs to 5T4 GCs, contributing to disturbances in olfactory behavior. Our novel findings suggest that, among the various types of OB interneurons, the 5T4 GC subtype is required for odor detection and discrimination behaviors. SIGNIFICANCE STATEMENT: Neuronal circuits in the brain include glutamatergic principal neurons and GABAergic interneurons. Although the latter is a minority cell type, they are vital for normal brain function because they regulate the activity of principal neurons. If interneuron function is impaired, brain function may be damaged, leading to behavior disorder. The olfactory bulb (OB) possesses various types of interneurons, including granule cells (GCs); however, the contribution that each type of interneuron makes to the control of olfactory behavior remains unknown. Here, we analyzed electrophysiologically and behaviorally the function of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic branching in OB GCs. We found that, among the various types of OB interneuron, the 5T4 GC subtype is required for odor detection and odor discrimination behaviors.


Assuntos
Interneurônios/citologia , Interneurônios/fisiologia , Odorantes/análise , Bulbo Olfatório/citologia , Bulbo Olfatório/fisiologia , Percepção Olfatória/fisiologia , Animais , Comportamento Animal/fisiologia , Aprendizagem por Discriminação/fisiologia , Interneurônios/classificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Bulbo Olfatório/embriologia
9.
Cancer Immunol Immunother ; 66(4): 415-426, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27757559

RESUMO

The natural history of a patient's cancer is often characterised by genetic diversity and sequential sweeps of clonal dominance. It is therefore not surprising that identifying the most appropriate tumour-associated antigen for targeted intervention is challenging. The 5T4 oncofoetal antigen was identified by searching for surface molecules shared between human trophoblast and cancer cells with the rationale that they may function to allow survival of the foetus as a semi-allograft in the mother or a tumour in its host. The 5T4 protein is expressed by many different cancers but rarely in normal adult tissues. 5T4 molecules are 72 kD, heavily N-glycosylated proteins with several leucine-rich repeats which are often associated with protein-protein interactions. 5T4 expression is associated with the directional movement of cells through epithelial mesenchymal transition, potentiation of CXCL12/CXCR4 chemotaxis and inhibition of canonical Wnt/beta-catenin while favouring non-canonical pathway signalling; all processes which help drive the spread of cancer cells. The selective pattern of 5T4 tumour expression, association with a tumour-initiating phenotype plus a mechanistic involvement with cancer spread have underwritten the clinical development of different immunotherapeutic strategies including a vaccine, a tumour-targeted superantigen and an antibody drug conjugate. In addition, a chimeric antigen receptor T cell approach targeting 5T4 expressing tumour cells is in pre-clinical development. A key challenge will include how best to combine each 5T4 targeted immunotherapy with the most appropriate standard of care treatment (or adjunct therapy) to maximise the recovery of immune control and ultimately eliminate the tumour.


Assuntos
Antígenos de Neoplasias/metabolismo , Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Glicoproteínas de Membrana/metabolismo , Neoplasias/terapia , Animais , Antígenos de Neoplasias/imunologia , Movimento Celular , Transição Epitelial-Mesenquimal , Humanos , Glicoproteínas de Membrana/imunologia , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/patologia
10.
Haematologica ; 102(6): 1075-1084, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28341731

RESUMO

Outcome in childhood acute lymphoblastic leukemia is prognosticated from levels of minimal residual disease after remission induction therapy. Higher levels of minimal residual disease are associated with inferior results even with intensification of therapy, thus suggesting that identification and targeting of minimal residual disease cells could be a therapeutic strategy. Here we identify high expression of 5T4 in subclonal populations of patient-derived xenografts from patients with high, post-induction levels of minimal residual disease. 5T4-positive cells showed preferential ability to overcome the NOD-scidIL2Rγnull mouse xenograft barrier, migrated in vitro on a CXCL12 gradient, preferentially localized to bone marrow in vivo and displayed the ability to reconstitute the original clonal composition on limited dilution engraftment. Treatment with A1mcMMAF (a 5T4-antibody drug conjugate) significantly improved survival without overt toxicity in mice engrafted with a 5T4-positive acute lymphoblastic leukemia cell line. Mice engrafted with 5T4-positive patient-derived xenograft cells were treated with combination chemotherapy or dexamethasone alone and then given A1mcMMAF in the minimal residual disease setting. Combination chemotherapy was toxic to NOD-scidIL2Rγnull mice. While dexamethasone or A1mcMMAF alone improved outcomes, the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (P=0.0006) over either monotherapy. These data show that specifically targeting minimal residual disease cells improved outcomes and support further investigation of A1mcMMAF in patients with high-risk B-cell precursor acute lymphoblastic leukemia identified by 5T4 expression at diagnosis.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Neoplasias/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea , Movimento Celular , Dexametasona/uso terapêutico , Xenoenxertos/patologia , Humanos , Camundongos , Terapia de Alvo Molecular/métodos , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prognóstico
11.
J Hand Surg Am ; 42(3): 175-181.e1, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28259274

RESUMO

PURPOSE: Limited literature supports using ethyl chloride topical spray as an anesthetic for hand injections whereas documented risks include frostbite, skin irritation, and inhalation toxicity. We hypothesize that ethyl chloride spray imparts no benefit to patients' perception of pain or anxiety for routine hand injections. METHODS: We first surveyed all members of the American Society for Surgery of the Hand to discern the prevalence of ethyl chloride use during routine injections. We then performed a prospective, randomized, study at 2 institutions evaluating the efficacy of ethyl chloride spray compared with "routine injection" (no topical spray) in patients indicated for a hand injection. All patients completed a pre- and postinjection 11-point questionnaire that inquired about various components of pain and anxiety. RESULTS: A total of 2,083 (73% response rate) American Society for Surgery of the Hand members responded to the survey and revealed that 59% of hand surgeons always or often use ethyl chloride, and 24% never use it. There were no differences for region or practice setting, but experienced surgeons were less likely to routinely use ethyl chloride (35%) compared with younger surgeons (66%). Among 151 patients participating in the clinical study (75 with ethyl chloride), there were no differences for any outcome measure assessed. Injection pain in the spray and no-spray groups, pain after 1 minute, and overall anxiety were equivalent. Subgroup analysis demonstrated no effect of sex, anticipated anxiety, or pain threshold. CONCLUSIONS: Ethyl chloride is widely used among hand surgeons but imparts no benefit for routine hand injections in the clinical setting. The potential risks and costs of ethyl chloride use may outweigh its benefits. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.


Assuntos
Anestésicos Locais/administração & dosagem , Cloreto de Etil/administração & dosagem , Mãos/cirurgia , Administração Tópica , Ansiedade , Crioterapia , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Medição da Dor , Percepção , Cuidados Pré-Operatórios , Estudos Prospectivos
12.
J Hand Surg Am ; 42(3): e209-e213, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28111061

RESUMO

Autograft tendon harvested from the long toe extensors are of great utility as intercalary grafts in upper extremity reconstruction. However, standard full-length harvest is complicated by the presence of extensor retinacula and multiple juncturae between adjacent extensors, which often necessitate extensive dissection, increasing the potential for morbidity. We describe a modified technique for partial harvest of the long toe extensors, which is performed entirely proximal to the superior extensor retinaculum. This technique requires a single incision and provides adequate length of graft for the majority of forearm to fingertip reconstructions. The technique is described in the context of our preliminary cadaver findings, with a case example provided to further illustrate the utility of this technique.


Assuntos
Traumatismos do Antebraço/cirurgia , Hallux/cirurgia , Traumatismos da Mão/cirurgia , Tendões/transplante , Coleta de Tecidos e Órgãos/métodos , Cadáver , Dissecação , Humanos , Tendões/cirurgia , Transplante Autólogo
13.
J Hand Surg Am ; 42(3): e149-e157, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28259279

RESUMO

PURPOSE: To investigate the anatomy of the volar surface of the proximal phalanx of the hand, specifically the longitudinal groove running along the volar phalangeal shaft. METHODS: We measured skeletonized proximal phalanges from 10 embalmed human cadaver hands at 5 equidistant points along the shaft. The difference between the maximum dorsal-palmar thickness of the shaft and thickness measured from the center of the volar groove to the most dorsal aspect of the phalanx indicated the depth of the groove at each point. These specimens underwent microtomography to characterize their osseous morphology further. Screws placed dorsal to palmar into the specimens and viewed fluoroscopically simulated the appearance of screw protrusion into the volar groove under intraoperative imaging. Similarly, screws placed into a fresh-frozen cadaveric hand illustrated possible screw impingement on soft tissue in vivo. RESULTS: The volar groove was most pronounced at the proximal and distal ends of the phalangeal shaft, becoming shallower along the midportion of the bone. The average difference between total bone thickness and thickness measured from the depth of the groove was significant at each of the 5 points of measurement along the phalangeal shaft for each of the 5 digits of the hand, including the thumb. Average groove depths ranged from 4% to 14% of total bone thickness, with a maximum individual measurement of 22%. Average depth of the groove at each of these positions ranged from 0.19 to 1.64 mm, reaching a maximum of 2.31 mm. CONCLUSIONS: We demonstrated that there is a longitudinal groove running the length of the phalangeal shaft. CLINICAL RELEVANCE: Viewed laterally, the cupped edges of the groove obscure its depth. Dorsally placed bicortical screws could protrude into the groove, remaining unnoticed on intraoperative imaging. The resulting impingement on the flexor tendon could lead to postsurgical stiffness or flexor tendon attritional rupture.


Assuntos
Traumatismos dos Dedos/cirurgia , Falanges dos Dedos da Mão/anatomia & histologia , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/cirurgia , Idoso , Idoso de 80 Anos ou mais , Parafusos Ósseos , Cadáver , Feminino , Falanges dos Dedos da Mão/lesões , Fixação Interna de Fraturas/instrumentação , Humanos , Masculino
14.
Semin Cancer Biol ; 29: 13-20, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25066861

RESUMO

Oncofoetal antigens are present during foetal development with generally limited expression in the adult but are upregulated in cancer. These molecules can sometimes be used to diagnose or follow treatment of tumours or as a target for different immunotherapies. The 5T4 oncofoetal glycoprotein was identified by searching for shared surface molecules of human trophoblast and cancer cells with the rationale that they may function to allow survival of the foetus as a semi-allograft in the mother or a tumour in its host, potentially influencing growth, invasion or altered immune surveillance of the host. 5T4 tumour selective expression has stimulated the development of 5T4 vaccine, 5T4 antibody targeted-superantigen and 5T4 antibody-drug therapies through preclinical and into clinical studies. It is now apparent that 5T4 expression is a marker of the use (or not) of several cellular pathways relevant to tumour growth and spread. Thus 5T4 expression is mechanistically associated with the directional movement of cells through epithelial mesenchymal transition, facilitation of CXCL12/CXCR4 chemotaxis, blocking of canonical Wnt/beta-catenin while favouring non-canonical pathway signalling. These processes are highly regulated in development and in normal adult tissues but can contribute to the spread of cancer cells. Understanding the differential impact of these pathways marked by 5T4 can potentially improve existing, or aid development of novel cancer treatment strategies.


Assuntos
Antígenos de Neoplasias/metabolismo , Vacinas Anticâncer/uso terapêutico , Transição Epitelial-Mesenquimal/fisiologia , Glicoproteínas de Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Biomarcadores Tumorais/metabolismo , Quimiocina CXCL12/metabolismo , Quimiotaxia/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Proteínas da Gravidez/metabolismo , Receptores CXCR4/metabolismo , Vacinas de DNA , Via de Sinalização Wnt/fisiologia
15.
J Cell Sci ; 125(Pt 22): 5467-78, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22956548

RESUMO

CXCL12 is a pleiotropic chemokine capable of eliciting multiple signal transduction cascades and functions, via interaction with either CXCR4 or CXCR7. Factors that determine CXCL12 receptor preference, intracellular signalling route and biological response are poorly understood but are of central importance in the context of therapeutic intervention of the CXCL12 axis in multiple disease states. We have recently demonstrated that 5T4 oncofoetal glycoprotein facilitates functional CXCR4 expression leading to CXCL12 mediated chemotaxis in mouse embryonic cells. Using wild type (WT) and 5T4 knockout (5T4KO) murine embryonic fibroblasts (MEFs), we now show that CXCL12 binding to CXCR4 activates both the ERK and AKT pathways within minutes, but while these pathways are intact, they are non-functional in 5T4KO cells treated with CXCL12. Importantly, in the absence of 5T4 expression, CXCR7 is upregulated and becomes the predominant receptor for CXCL12, activating a distinct signal transduction pathway with slower kinetics involving transactivation of the epidermal growth factor receptor (EGFR), eliciting proliferation rather than chemotaxis. Thus the surface expression of 5T4 marks the use of the CXCR4 rather than the CXCR7 receptor, with distinct consequences for CXCL12 exposure, relevant to the spread and growth of a tumour. Consistent with this hypothesis, we have identified human small cell lung carcinoma cells with similar 5T4/CXCR7 reciprocity that is predictive of biological response to CXCL12 and determined that 5T4 expression is required for functional chemotaxis in these cells.


Assuntos
Antígenos de Neoplasias/metabolismo , Antígenos de Superfície/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Quimiotaxia/efeitos dos fármacos , Embrião de Mamíferos/citologia , Receptores ErbB/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Quinases da Família src/metabolismo
16.
Instr Course Lect ; 63: 131-42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24720301

RESUMO

Dupuytren contracture is a condition that affects the palmar fascia. It most commonly affects men of northern European ancestry and initially presents at middle age. The diseased fascia may form cords that extend into the digits, resulting in limited motion and function. Treatment is aimed at either releasing or removing the diseased cord so that the finger can extend fully. Common interventions include surgery, needle aponeurotomy, and collagenase injection. Surgery remains the gold standard in treatment and most commonly includes a limited fasciectomy. Although often successful, surgery carries inherent risks and may involve a lengthy recovery with extensive therapy. Needle aponeurotomy and collagenase injections are office-based alternatives that aim to weaken the cord and release the contracture. Needle aponeurotomy involves repeated needling along the cord in intervals and collagenase injections to dissolve a portion of the cord. Despite being less invasive, problems such as nerve and/or tendon injury, skin tears, and autoimmune reactions have been reported. Regardless of treatment, recurrence remains a concern.


Assuntos
Contratura de Dupuytren/terapia , Fatores Etários , Colagenases/uso terapêutico , Contratura de Dupuytren/diagnóstico , Contratura de Dupuytren/etiologia , Fasciotomia , Humanos , Fatores Sexuais , Transplante de Pele , Resultado do Tratamento
17.
Instr Course Lect ; 63: 97-103, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24720297

RESUMO

Orthopaedic and hand surgeons frequently treat disorders of the flexor and extensor tendon systems. Common conditions, such as trigger finger, de Quervain tenosynovitis, extensor tendon injury, and zone II flexor tendon injury, can be challenging to treat. Complications that limit normal hand function still occur despite advances in surgical techniques and therapy protocols. It is helpful to be aware of the complications related to the treatment of these hand disorders and understand surgical techniques to minimize their frequency.


Assuntos
Traumatismos da Mão/cirurgia , Erros Médicos/efeitos adversos , Complicações Pós-Operatórias , Tendinopatia/cirurgia , Traumatismos do Punho/cirurgia , Traumatismos da Mão/diagnóstico , Traumatismos da Mão/etiologia , Humanos , Tendinopatia/diagnóstico , Tendinopatia/etiologia , Traumatismos do Punho/diagnóstico , Traumatismos do Punho/etiologia
18.
Instr Course Lect ; 63: 105-11, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24720298

RESUMO

Iatrogenic nerve injuries frequently occur during procedures around the hand and wrist, although they are not always recognized at the time of injury or in the immediate postoperative period. Because preventing injuries is of paramount importance, extensive knowledge of the anatomy of the at-risk nerves is critical. Best results occur after immediate repair because a substantial delay before secondary surgery diminishes the chances for recovery from motor or sensory nerve dysfunction and relief from pain. It is helpful to review iatrogenic nerve injuries associated with common hand surgical procedures.


Assuntos
Traumatismos do Braço/etiologia , Doença Iatrogênica , Erros Médicos/efeitos adversos , Doenças Musculoesqueléticas/cirurgia , Traumatismos dos Nervos Periféricos/etiologia , Complicações Pós-Operatórias , Traumatismos do Braço/diagnóstico , Traumatismos do Braço/cirurgia , Humanos , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/etiologia , Traumatismos dos Nervos Periféricos/diagnóstico , Traumatismos dos Nervos Periféricos/cirurgia , Extremidade Superior
19.
Instr Course Lect ; 63: 113-22, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24720299

RESUMO

Fractures of the distal radius and the scaphoid are common injuries in adults. In recent years, surgical fixation of these types of fractures has increased in response to improved patient outcomes and evolving fixation techniques. Potential soft-tissue, neurovascular, or osseous complications, including tendon injuries, carpal tunnel syndrome, loss of fracture reduction, and osteonecrosis, can increase the time the patient requires immobilization and can lead to poor patient outcomes. Prompt recognition and diagnosis of these complications may improve patient outcomes and satisfaction.


Assuntos
Fixação Interna de Fraturas/efeitos adversos , Traumatismos dos Nervos Periféricos/etiologia , Fraturas do Rádio/cirurgia , Osso Escafoide/lesões , Traumatismos dos Tendões/etiologia , Traumatismos do Punho/etiologia , Humanos , Traumatismos dos Nervos Periféricos/diagnóstico , Osso Escafoide/cirurgia , Traumatismos dos Tendões/diagnóstico , Traumatismos do Punho/diagnóstico
20.
Instr Course Lect ; 63: 123-30, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24720300

RESUMO

Dorsal fracture-dislocations of the proximal interphalangeal joint are challenging injuries to treat and are associated with many complications. The determination of stability is crucial to appropriate management. Stable injuries can usually be treated nonsurgically, whereas unstable injuries typically require surgical stabilization. Many surgical techniques have been used, including extension block pinning, volar plate arthroplasty, open reduction and internal fixation, external fixation, and hemihamate autografting. Because stiffness and flexion contracture are frequent complications, every effort should be made to initiate early motion while maintaining concentric reduction. Other complications include redislocation, chronic swelling, swan neck and coronal plane deformities, and pin tract infections. Assessing injury characteristics, including chronicity, the percentage of articular surface fractured, and the degree of comminution, and understanding complications will help in determining the most appropriate treatment. Chronic dislocations and those injuries in which painful arthritis develops can be successfully treated with salvage procedures, including arthroplasty and arthrodesis.


Assuntos
Traumatismos dos Dedos/complicações , Articulações dos Dedos , Fraturas Intra-Articulares/complicações , Luxações Articulares/complicações , Traumatismos dos Dedos/diagnóstico , Traumatismos dos Dedos/terapia , Humanos , Fraturas Intra-Articulares/diagnóstico , Fraturas Intra-Articulares/terapia , Luxações Articulares/diagnóstico , Luxações Articulares/terapia
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