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BACKGROUND: Laparoscopic cholecystectomy is a very frequent surgical procedure. However, in an ageing society, less surgical staff will need to perform surgery on patients. Collaborative surgical robots (cobots) could address surgical staff shortages and workload. To achieve context-awareness for surgeon-robot collaboration, the intraoperative action workflow recognition is a key challenge. METHODS: A surgical process model was developed for intraoperative surgical activities including actor, instrument, action and target in laparoscopic cholecystectomy (excluding camera guidance). These activities, as well as instrument presence and surgical phases were annotated in videos of laparoscopic cholecystectomy performed on human patients (n = 10) and on explanted porcine livers (n = 10). The machine learning algorithm Distilled-Swin was trained on our own annotated dataset and the CholecT45 dataset. The validation of the model was conducted using a fivefold cross-validation approach. RESULTS: In total, 22,351 activities were annotated with a cumulative duration of 24.9 h of video segments. The machine learning algorithm trained and validated on our own dataset scored a mean average precision (mAP) of 25.7% and a top K = 5 accuracy of 85.3%. With training and validation on our dataset and CholecT45, the algorithm scored a mAP of 37.9%. CONCLUSIONS: An activity model was developed and applied for the fine-granular annotation of laparoscopic cholecystectomies in two surgical settings. A machine recognition algorithm trained on our own annotated dataset and CholecT45 achieved a higher performance than training only on CholecT45 and can recognize frequently occurring activities well, but not infrequent activities. The analysis of an annotated dataset allowed for the quantification of the potential of collaborative surgical robots to address the workload of surgical staff. If collaborative surgical robots could grasp and hold tissue, up to 83.5% of the assistant's tissue interacting tasks (i.e. excluding camera guidance) could be performed by robots.
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Colecistectomia Laparoscópica , Aprendizado de Máquina , Procedimentos Cirúrgicos Robóticos , Colecistectomia Laparoscópica/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Humanos , Suínos , Animais , Algoritmos , Gravação em Vídeo , Fluxo de TrabalhoRESUMO
AIM: We aimed to determine stillbirth, preterm birth, perinatal complications, and the developmental outcome of children born preterm during the COVID-19 pandemic in Germany. METHODS: National data from the perinatal survey of preterm and term infants born in 2017-2020 between 22 March and 31 December were evaluated. Neurodevelopment of preterm infants at 2 years corrected age was tested with the Parent Report of Children's Abilities-Revised questionnaire and by clinical testing with Bayley scales, either before or during the COVID-19 pandemic. Statistical significance was calculated using a Pearson's chi-square-independence test and a linear regression model. RESULTS: In 2020, there was an increase of stillbirths of 0.02% (p = 0.01) and a decrease in preterm births by 0.38% (p < 0.001). No changes were found in a representative subgroup of infants with regard to neurodevelopmental scores (mental developmental index and psychomotor developmental index) or in parent survey data (non-verbal cognition scale and language development scale). CONCLUSION: Increasing rates of stillbirths and decreasing preterm births in Germany were observed. Existing networks might stabilise neurodevelopment of preterm infants during the COVID-19 pandemic.
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COVID-19 , Nascimento Prematuro , Lactente , Gravidez , Feminino , Criança , Recém-Nascido , Humanos , Recém-Nascido Prematuro , Nascimento Prematuro/epidemiologia , Desenvolvimento Infantil , Natimorto/epidemiologia , Pandemias , COVID-19/epidemiologiaRESUMO
BACKGROUND: Laparoscopic videos are increasingly being used for surgical artificial intelligence (AI) and big data analysis. The purpose of this study was to ensure data privacy in video recordings of laparoscopic surgery by censoring extraabdominal parts. An inside-outside-discrimination algorithm (IODA) was developed to ensure privacy protection while maximizing the remaining video data. METHODS: IODAs neural network architecture was based on a pretrained AlexNet augmented with a long-short-term-memory. The data set for algorithm training and testing contained a total of 100 laparoscopic surgery videos of 23 different operations with a total video length of 207 h (124 min ± 100 min per video) resulting in 18,507,217 frames (185,965 ± 149,718 frames per video). Each video frame was tagged either as abdominal cavity, trocar, operation site, outside for cleaning, or translucent trocar. For algorithm testing, a stratified fivefold cross-validation was used. RESULTS: The distribution of annotated classes were abdominal cavity 81.39%, trocar 1.39%, outside operation site 16.07%, outside for cleaning 1.08%, and translucent trocar 0.07%. Algorithm training on binary or all five classes showed similar excellent results for classifying outside frames with a mean F1-score of 0.96 ± 0.01 and 0.97 ± 0.01, sensitivity of 0.97 ± 0.02 and 0.0.97 ± 0.01, and a false positive rate of 0.99 ± 0.01 and 0.99 ± 0.01, respectively. CONCLUSION: IODA is able to discriminate between inside and outside with a high certainty. In particular, only a few outside frames are misclassified as inside and therefore at risk for privacy breach. The anonymized videos can be used for multi-centric development of surgical AI, quality management or educational purposes. In contrast to expensive commercial solutions, IODA is made open source and can be improved by the scientific community.
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Inteligência Artificial , Laparoscopia , Humanos , Privacidade , Laparoscopia/métodos , Algoritmos , Redes Neurais de Computação , Gravação em VídeoRESUMO
BACKGROUND: Digital systems have increasingly become integrated into the modern operating room in the last few decades. This has brought about a massive change, especially in minimally invasive surgery. OBJECTIVE: The article provides an overview of the current technical innovations and the perspectives of digitalization and artificial intelligence (AI) in surgery. MATERIAL AND METHODS: The article is based on a literature search via PubMed and research work by the participating coauthors. RESULTS: Current research is increasingly looking at machine learning techniques that take advantage of the complex data in surgery; however, the integration of artificial intelligence systems into the operating room and clinical practice has only just begun. DISCUSSION: Translational research of artificial intelligence in surgery is still in its infancy but has great potential to improve patient care; however, to accelerate the incorporation of intelligent systems into the clinical practice, the creation of interdisciplinary research groups led by surgeons is necessary.
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Inteligência Artificial , Cirurgiões , Previsões , Humanos , Salas CirúrgicasRESUMO
Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.
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Colesterol , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias da Próstata , Esqualeno Mono-Oxigenase , Idoso , Idoso de 80 Anos ou mais , Animais , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular , Colesterol/biossíntese , Estudos de Coortes , Simulação por Computador , Modelos Animais de Doenças , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Esqualeno Mono-Oxigenase/genética , Esqualeno Mono-Oxigenase/metabolismo , Terbinafina/farmacologia , Ativação Transcricional/genéticaRESUMO
BACKGROUND: Apremilast is an oral phosphodiesterase-4 inhibitor indicated for patients with moderate-to-severe chronic plaque psoriasis and active psoriatic arthritis. OBJECTIVES: To examine the effectiveness of apremilast on Dermatology Life Quality Index (DLQI), Psoriasis Area and Severity Index (PASI) and nail, scalp and palmoplantar involvement, when administered prior to biologics. METHODS: This 52-week real-world study included biologic-naive adults with moderate psoriasis (psoriasis-involved body surface area 10% to <20%, or PASI 10 to <20 and DLQI 10 to <20). Apremilast was initiated ≤7 days before enrolment. Data from the first 100 eligible patients who completed 24 weeks (W24) of observation (or were prematurely withdrawn) are presented in this interim analysis using the last-observation-carried-forward imputation method. RESULTS: Eligible patients (mean age: 49.9 years; 71.0% males; median disease duration: 8.0 years) were consecutively enrolled between April and October 2017, by 18 dermatology specialists practising in hospital outpatient settings in Greece. Baseline DLQI (median: 12.0) and PASI (median: 11.7) scores improved (P < 0.001) at all postbaseline timepoints (Weeks 6, 16 and 24; W24 median decreases: 9.0 and 9.4 points respectively). At W24, DLQI ≤5, DLQI 0 or 1, and PASI-75 response rates were 63.0%, 25.0% and 48.0% respectively. The Nail Psoriasis Severity Index score in patients with baseline nail involvement (n = 57) decreased at all postbaseline timepoints (P < 0.001; W24 median decrease: 20.0 points). At W24, 50.0% and 51.7% of patients with baseline scalp (n = 76) and palmoplantar (n = 29) involvement respectively achieved postbaseline Physician's Global Assessment (PGA) score of 0 or 1 if baseline score was ≥3, or 0 if baseline score was 1 or 2. The adverse drug reaction rate was 21.0% (serious: 2.0%). CONCLUSIONS: These interim results indicate that through 24 weeks, apremilast improved quality of life and reduced disease severity in biologic-naive patients with moderate plaque psoriasis, while demonstrating safety consistent with the known safety profile.
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Produtos Biológicos , Psoríase , Adulto , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Qualidade de Vida , Índice de Gravidade de Doença , Talidomida/análogos & derivados , Resultado do TratamentoRESUMO
BACKGROUND: Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. OBJECTIVES: To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. METHODS: Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. RESULTS: In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. CONCLUSIONS: Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.
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Pênfigo , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Autoanticorpos , Humanos , Pênfigo/tratamento farmacológico , PrednisonaRESUMO
BACKGROUND: The importance of the apophyseal plates during growth is often underestimated. They act as a muscular insertion and influence the joint mechanics by the load-dependent change in shape. PATHOMECHANISMS: An anatomically functional adaptation occurs as protection from overloading. In special kinds of sports with highly dynamic movements, sudden changes of direction and eccentric/concentric muscle activities the resulting stress may exceed the strength of the apophyseal plate. In adolescence this results in a total or partial tearing of the apophysis in the sense of an avulsion injury. In the pelvic region the ischial tuberosity, the anterior superior and inferior iliac spine are mainly affected. DIAGNOSTICS: The medical history and clinical diagnostics are supplemented by conventional radiographic imaging. Sectional imaging diagnostics are usually unnecessary. TREATMENT: Conservative management by reduced (partial) weight bearing and physiotherapy represents the gold standard in treatment. In cases with a fragment displacementâ¯>1.5-2.0â¯cm and in competitive athletes an open reduction should be considered.
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Traumatismos em Atletas , Fratura Avulsão , Fraturas Ósseas , Adolescente , Traumatismos em Atletas/diagnóstico por imagem , Traumatismos em Atletas/terapia , Fratura Avulsão/diagnóstico por imagem , Fratura Avulsão/cirurgia , Humanos , Ísquio/lesões , PelveRESUMO
Climate models predict an increase in extent, frequency, and duration of marine hypoxia events in the twenty first century. A better understanding of organismal responses to hypoxia in individual species is a crucial step for predicting ecosystem responses. We experimentally subjected a common invertebrate, the bearded fireworm (Hermodice carunculata) to two levels of chronic hypoxia and, in a separate experiment, to intermittent hypoxia. We found components of the conserved hypoxia-inducible factor (HIF) pathway and show a modulated response to hypoxia depending on the severity of hypoxic stress: under mild hypoxia, only the HIF-1α subunit is upregulated, while expression of the other subunit, aryl hydrocarbon nuclear translator, only increases significantly at more severe hypoxia levels. The chronic trials revealed down-regulation of genes related to cell adhesion, transport, development and heme-binding, and up-regulation of genes related to glycolysis, oxygen binding, cell differentiation, digestive and reproductive function. The intermittent hypoxia trials revealed an upregulation of heme transporter activity during hypoxia, and our time series analysis characterized nine clusters of genes with similar expression patterns. Our findings suggest that H. carunculata is likely to tolerate, and be resilient to, predicted future hypoxia conditions.
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Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipóxia/genética , Poliquetos/genética , Animais , Diferenciação Celular/fisiologia , Hipóxia Celular/fisiologia , Glicólise/fisiologia , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Poliquetos/metabolismo , Regulação para CimaRESUMO
Wearing face masks reduce the maximum physical performance. Sports and occupational activities are often associated with submaximal constant intensities. This prospective crossover study examined the effects of medical face masks during constant-load exercise. Fourteen healthy men (age 25.7 ± 3.5 years; height 183.8 ± 8.4 cm; weight 83.6 ± 8.4 kg) performed a lactate minimum test and a body plethysmography with and without masks. They were randomly assigned to two constant load tests at maximal lactate steady state with and without masks. The cardiopulmonary and metabolic responses were monitored using impedance cardiography and ergo-spirometry. The airway resistance was two-fold higher with the surgical mask (SM) than without the mask (SM 0.58 ± 0.16 kPa l-1 vs. control [Co] 0.32 ± 0.08 kPa l-1; p < 0.01). The constant load tests with masks compared with those without masks resulted in a significantly different ventilation (77.1 ± 9.3 l min-1 vs. 82.4 ± 10.7 l min-1; p < 0.01), oxygen uptake (33.1 ± 5 ml min-1 kg-1 vs. 34.5 ± 6 ml min-1 kg-1; p = 0.04), and heart rate (160.1 ± 11.2 bpm vs. 154.5 ± 11.4 bpm; p < 0.01). The mean cardiac output tended to be higher with a mask (28.6 ± 3.9 l min-1 vs. 25.9 ± 4.0 l min-1; p = 0.06). Similar blood pressure (177.2 ± 17.6 mmHg vs. 172.3 ± 15.8 mmHg; p = 0.33), delta lactate (4.7 ± 1.5 mmol l-1 vs. 4.3 ± 1.5 mmol l-1; p = 0.15), and rating of perceived exertion (6.9 ± 1.1 vs. 6.6 ± 1.1; p = 0.16) were observed with and without masks. Surgical face masks increase airway resistance and heart rate during steady state exercise in healthy volunteers. The perceived exertion and endurance performance were unchanged. These results may improve the assessment of wearing face masks during work and physical training.
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Resistência das Vias Respiratórias , Pressão Sanguínea , Exercício Físico , Frequência Cardíaca , Ácido Láctico/sangue , Máscaras , Resistência Física , Adulto , Estudos Cross-Over , Humanos , MasculinoRESUMO
BACKGROUND: Branched-chain amino acid (BCAA) concentrations must be tracked and maintained within an optimal range to minimize disease phenotypes in patients with maple syrup urine disease (MSUD). In 2014, the Hospital for Sick Children (SickKids) implemented a dried blood spot (DBS) home monitoring system, allowing patients to track BCAA concentrations without the inconvenience of having to travel to the hospital. METHODS: We conducted a retrospective chart review study (nâ¯=â¯15) to assess the impacts of DBS monitoring implementation on biochemical control. Furthermore, we explored relationships among various MSUD patient parameters, including monitoring frequency, age, biochemical control, and hospitalizations. RESULTS: There was a 35% increase in the proportion of LEU concentrations that met recommended targets post-DBS monitoring implementation. Monitoring frequency was positively associated with better biochemical control in the newborn period (râ¯=â¯0.68, pâ¯=â¯0.046). Frequency of hospital visits decreased steadily throughout life. CONCLUSION: DBS monitoring has resulted in a sharp increase in monitoring frequency, which is further correlated with biochemical control. Younger patients are more likely to visit the hospital and respond better to increased monitoring efforts. We recommend that DBS monitoring be adopted by other centers more broadly to improve metabolic control in MSUD patients.
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Aminoácidos de Cadeia Ramificada/sangue , Teste em Amostras de Sangue Seco , Doença da Urina de Xarope de Bordo/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Doença da Urina de Xarope de Bordo/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Genetic causes of skeletal disorders are manifold and affect, among others, enzymes of bone and connective tissue synthesis pathways. We present a twelve-year-old boy with a mild skeletal dysplasia, hypermobility of joints and axial malalignment of lower limbs and feet. Exome sequencing revealed a biallelic loss of function mutation in CSGALNACT1, which encodes chondroitin sulfate N-acetylgalactosaminyltransferase 1 and plays a major role in the chondroitin sulfate chain biosynthesis and therefore in the synthesis of glycosaminoglycans. Recently, the first case of a pediatric patient with a mild skeletal dysplasia due to a compound heterozygous large intragenic deletion and a damaging missense variant in CSGALNACT1 was reported. We here identify a second case and the first juvenile patient with a homozygous frameshift variant in CSGALNACT1 which corroborates its role in mild and non-progressive skeletal dysplasia with joint laxity.
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Alelos , Mutação/genética , N-Acetilgalactosaminiltransferases/genética , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Estatura , Peso Corporal , Criança , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagemRESUMO
BACKGROUND: Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by urticarial exanthema, bone and joint alterations, fever and monoclonal gammopathy, which manifest mostly in the second half of life. It involves overactivation of the interleukin (IL)-1 system, but the exact pathophysiological pathways remain largely unknown. OBJECTIVES: To identify and characterize the pathogenetic players in SchS. METHODS: Blood parameters were quantified in patients with SchS compared with healthy controls and patients with psoriasis and hidradenitis suppurativa using enzyme-linked immunosorbent assay (ELISA). CCL2 expression in cultured primary cells was analysed by quantitative reverse-transcriptase polymerase chain reaction and ELISA. RESULTS: CCL2, a chemoattractant for monocytic and further mononuclear immune cells, was found to be significantly elevated in patients with SchS. CCL2 levels showed a positive association with global disease activity, especially with bone pain, but not disease duration, gammopathy, neutrophilia or skin disease. In vitro stimulation assays demonstrated a strong CCL2 production capacity of mononuclear immune cells and fibroblasts, but not epithelial or endothelial cells. Among a range of inflammatory mediators, only IL-1ß (immune cells, fibroblasts) and tumour necrosis factor (TNF)-α (fibroblasts) were important CCL2 inducers. TNF-α, but not IL-17, strengthened the CCL2-inducing effect of IL-1ß in fibroblasts. Accordingly, CCL2 levels positively correlated with both TNF-α and IL-1ß serum levels in patients with SchS. Therapeutic IL-1ß blockade decreased CCL2 blood levels in these patients as early as 1 week after the initiation of treatment. CONCLUSIONS: CCL2 may be an important component of the pathogenetic cascade leading to bone alterations, and a suitable marker of disease activity in patients with SchS.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Quimiocina CCL2/sangue , Interleucina-1beta/antagonistas & inibidores , Dor Musculoesquelética/diagnóstico , Síndrome de Schnitzler/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Voluntários Saudáveis , Hidradenite Supurativa/sangue , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/sangue , Dor Musculoesquelética/tratamento farmacológico , Dor Musculoesquelética/imunologia , Cultura Primária de Células , Psoríase/sangue , Síndrome de Schnitzler/sangue , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Legg-Calvé-Perthes disease is a multifactorial idiopathic necrosis of the hip that typically occurs in childhood between the ages of 3 and 12. Treatment adapted to the stadium of the disease and to the clinical findings is medical art. The treatment is focused on the preservation or recovery of the arthrogenic containment of the femoral head. Multiple treatment options are available. The indications for treatment can be derived from clinical and radiological pathology. Structuring of the therapy options is the aim of this publication. For this purpose, a clear and concise overview of relevant clinical findings and useful radiographic classifications as well as reasonable therapy is presented.
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Algoritmos , Necrose da Cabeça do Fêmur , Doença de Legg-Calve-Perthes , Criança , Pré-Escolar , Cabeça do Fêmur , Humanos , Doença de Legg-Calve-Perthes/diagnóstico , Doença de Legg-Calve-Perthes/terapia , RadiografiaRESUMO
OBJECTIVES: The influence of blood group antigens on cancerogenesis is shown for distinct tumor types, yet the impact of Rhesus blood group antigens in lung cancer is not clarified. MATERIALS AND METHODS: To investigate the impact of Rhesus blood groups a non-small cell lung cancer (NSCLC) collective (n = 1047) was analyzed retrospectively. Using a second cohort of n = 340 primarily operated stage I-III NSCLC patients, we evaluated immunohistochemistry of CD47-antibody stained tissue samples in correlation to histopathologic subtype and Rhesus blood group. RESULTS AND CONCLUSION: In 516 of 1047 patients blood group data were available. Seven different RhCE phenotypes were grouped as "··ee," "ccE·," and "C·E·." Adenocarcinoma patients with Rh "··ee" revealed improved overall survival (29 (21.2-36.8) m; HR 1.00 [index]) compared with Rh "ccE·" (19 (1.9-36.1) m; HR 1.76 [1.15-2.70]) and Rh "C·E·" (10 (7.4-12.6) m; HR 2.65 [1.70-4.12]) univariately (P < .001) and multivariately (P < .001). Rh "··ee" showed reduced incidence of CNS-metastasis (P = .014) and metastasis count (P = .032) in stage IV adenocarcinoma. Immunohistochemistry associated CD47-positivity with adenocarcinomas (n = 340, P = .048). In n = 51 cases blood group data were available. The prognostic effect of Rh "··ee" compared with Rh "ccE·" and Rh "C·E·" was stated (P = .001), foremost in CD47-positive adenocarcinomas (Rh "··ee" vs. Rh "ccE·" and Rh "C·E·," P = .008). Inversely Rh "ccE·" or Rh "C·E·" was found beneficial in CD47-negative non-adenocarcinomas (P = .046). Phenotypic RhCE expression may be an independent prognostic factor for overall survival in adeno-NSCLC. We hypothesize an erythrocytic-immunologic interaction with tumor tissue, possibly altered by RhCE and CD47, resulting in a metastatic prone condition.
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Carcinoma Pulmonar de Células não Pequenas/sangue , Eritrócitos/metabolismo , Neoplasias Pulmonares/sangue , Estadiamento de Neoplasias , Sistema do Grupo Sanguíneo Rh-Hr/biossíntese , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Feminino , Alemanha/epidemiologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida/tendênciasRESUMO
The performance of heterogeneous 3D transistor structures critically depends on the composition and strain state of the buffer, channel and source/drain regions. In this paper we used an in-line high resolution x-ray diffraction (HRXRD) tool to study in detail the composition and strain in selectively grown SiGe/Ge fin structures with widths down to 20 nm. For this purpose we arranged fins of identical dimensions into larger arrays which were then analyzed using an x-ray beam several tens of micrometers in size. Asymmetric reciprocal space maps measured both parallel and perpendicular to the fins allowed us to extract the lattice parameters in all three spatial directions. Our results demonstrate an anisotropic in-plane strain state of the selectively grown SiGe buffer in case of narrower fins with significantly reduced relaxation in the direction along the fin. This observation was verified using nano-beam electron diffraction, and is explained based on the reduced probability for dislocation half-loops to evolve in trenches narrower than a few times the critical radius. Moreover, we introduce and discuss in detail a methodology for the determination of the composition in case of an anisotropic in-plane strain state which differs from the procedure commonly used for blanket layers. Our findings verify the importance of in-line HRXRD measurements for process development and monitoring as well as the fundamental study of relaxation and defect formation in confined volumes.
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The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53-deficient cancer cells increased levels of the allosteric regulator fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment.