RESUMO
BACKGROUND: HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question. METHODS: We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on hearts and isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation. RESULTS: We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo. CONCLUSIONS: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
RESUMO
Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias Primárias Desconhecidas , Humanos , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/patologia , Estudos Prospectivos , Estudos Retrospectivos , Austrália , Perfilação da Expressão Gênica , Análise de Sequência de DNA , RNARESUMO
The present study analyses the effect of age at first calving (AFC) on future fertility and productivity in Murrah buffaloes. The data of 314 buffalo heifers of animal farm section, ICAR-CIRB, Hisar were collected over a period of 9 years from 2010 to 2018. The buffalo heifers were categorized into six groups according to the AFC named as 30-35, 36-41, 42-47, 48-53, 54-59 and 60-65 months. The influence of AFC on standard lactation milk (SLMY), peak yield (PY), days in milk (DIM), calving to first service, service per conception, calving to conception interval (CCI) and calving interval till fifth lactation were studied. The study revealed poor productive traits in buffalo heifers calved at younger age (30-35 months) during first parity. The productive value positively corresponded with increase in AFC. During successive lactations, higher mean milk yield (SLMY and PY) was found in groups with 36-41, 42-47 and 48-53 months. The mean number of services per conception was lower in buffalo heifers with 36-41 and 42-47 months following first calving till fifth lactation. Similarly, the said groups had lower mean calving to first service, CCI and CI up to fifth lactation. The survival rate was higher in heifers with AFC 36-41, 42-47, 48-53 and 54-59 months than with AFC 30-35 and 60-65 months. The buffalo heifers with 36-41 and 42-47 months of AFC had higher survival rate and better productive and reproductive traits till fifth parity in the current study. The study concluded that a minimum ideal AFC of 36-41 months yielded the highest productive gain.
Assuntos
Búfalos , Fertilidade , Lactação , Leite , Animais , Búfalos/fisiologia , Feminino , Lactação/fisiologia , Gravidez , Fatores EtáriosRESUMO
INTRODUCTION: Peripheral arterial disease (PAD) occurs from atherosclerotic obstruction of arteries in the lower extremities. Restoration of perfusion requires angiogenesis and arteriogenesis through migration and differentiation of endothelial progenitor cells (EPCs) and macrophages at the site of injury. The time of recruitment has not been fully investigated. In this study, we investigated the infiltration of these cells in murine hind limb ischemia (HLI) model of PAD. METHODS: EPCs and M1-like and M2-like macrophages from ischemic skeletal muscles were quantified by flow cytometry at day-0, 1, 3, 7, and 14 post-HLI. RESULTS: The abundance of EPCs increased from day 1 and was highest on day 7 until day 14. M1-like population similarly increased and was highest on day 14 during the experiment. M2-like population was significantly greater than M1-like at baseline but surpassed the highest value of M1-like by day 7 during the experiment. Muscle regeneration and capillary density also increased and were highest at days 3 and 7, respectively, during the experiment. All mice achieved near full perfusion recovery by day 14. CONCLUSION: Thus, we observed a gradual increase in the percentage of EPC's and this was temporally paralleled with initial increase in M1-like followed by sustained increased in M2-like macrophages and perfusion recovered post-HLI.
Assuntos
Células Progenitoras Endoteliais , Doença Arterial Periférica , Camundongos , Animais , Isquemia , Artérias , Membro Posterior/irrigação sanguínea , Macrófagos , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
A rigid tetracene dimer with a substantial interchromophore distance has been prepared through an application of the recently developed catalytic arene-norbornene annulation (CANAL) reaction. An iterative cycloaddition route was found to be unsuccessful, so a shorter route was adopted whereby fragments were coupled in the penultimate step to form a 13:1 mixture of two diastereomers, the major of which was isolated and crystallized. Constituent tetracene moieties are linked with a rigid, well-defined bridge and feature a near-co-planar mutual orientation of the acenes.
RESUMO
OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer ' and asked ' how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.
Assuntos
Neoplasias Primárias Desconhecidas , Qualidade de Vida , Estudos Transversais , Necessidades e Demandas de Serviços de Saúde , Humanos , Neoplasias Primárias Desconhecidas/psicologia , Qualidade de Vida/psicologia , Inquéritos e Questionários , IncertezaRESUMO
Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus , Angiopatias Diabéticas , Neuropatias Diabéticas , Doença Arterial Periférica , Animais , Proteínas Reguladoras de Apoptose/genética , Diabetes Mellitus/metabolismo , Angiopatias Diabéticas/metabolismo , Neuropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Membro Posterior/irrigação sanguínea , Humanos , Isquemia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Necroptose , Doença Arterial Periférica/genética , Doença Arterial Periférica/metabolismoRESUMO
OBJECTIVE: For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. DESIGN: We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4-10 weeks after surgery. Somatic mutations in individual patient's tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. RESULTS: We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). CONCLUSION: Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.
Assuntos
Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Neoplasias Retais/genética , Neoplasias Retais/terapia , Austrália , Terapia Combinada , Diagnóstico por Imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias Retais/sangue , Neoplasias Retais/patologia , Sistema de Registros , Fatores de Risco , Análise de SobrevidaRESUMO
Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-ß (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg-1·min-1 for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice (Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice (Tlr3-/-), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways. NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-ß (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.
Assuntos
Angiotensina II , Cardiomegalia/metabolismo , Hipertensão/metabolismo , Imunidade Inata , Rim/metabolismo , Miocárdio/metabolismo , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/imunologia , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/imunologia , Mediadores da Inflamação/metabolismo , Rim/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/imunologia , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genéticaRESUMO
BACKGROUND: Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated. OBJECTIVE: We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161+ immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor γt (RORγt) and a nicotinic proinflammatory innate immune response. METHODS: We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs. RESULTS: SHRs exhibited an abnormally large population of CD161+ cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38 weeks. The SHR splenocytes constitutively expressed more RORγt than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, in vivo inhibition of RORγt by digoxin decreased systolic blood pressure in SHRs. CONCLUSIONS: SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.
Assuntos
Hipertensão/imunologia , Interleucina-17/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Envelhecimento/imunologia , Animais , Animais Recém-Nascidos , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Digoxina/farmacologia , Hipertensão/fisiopatologia , Interleucina-17/genética , Interleucina-17/fisiologia , Masculino , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Poli I-C/farmacologia , RNA/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Baço/citologia , Receptor 3 Toll-Like/agonistas , VasodilataçãoRESUMO
Venous air embolism can be a catastrophic iatrogenic complication during operative hysteroscopy and makes this simple surgical procedure very risky, especially with the lack of knowledge about its prevention, presentation, and immediate management. Three out of 13 hysteroscopic myoma resections at our center had venous gas embolism (VGE). The prevention, diagnosis, and management of VGE are described in this report of three cases.
RESUMO
The autonomic nervous system is a powerful regulator of circulatory adjustments to acute hemodynamic stresses. Here we focus on new concepts that emphasize the chronic influence of the sympathetic and parasympathetic systems on cardiovascular pathology. The autonomic neurohumoral system can dramatically influence morbidity and mortality from cardiovascular disease through newly discovered influences on the innate and adaptive immune systems. Specifically, the end-organ damage in heart failure or hypertension may be worsened or alleviated by pro- or anti-inflammatory pathways of the immune system, respectively, that are activated through neurohumoral transmitters. These concepts provide a major new perspective on potentially life-saving therapeutic interventions in the deadliest of diseases.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Doenças Cardiovasculares/imunologia , Sistema Imunitário/fisiologia , Imunidade Inata/fisiologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/fisiologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/imunologia , Sistema Cardiovascular/fisiopatologia , Citocinas/imunologia , Citocinas/metabolismo , Hemodinâmica/fisiologia , Humanos , Sistema Imunitário/fisiopatologia , Neurotransmissores/imunologia , Neurotransmissores/metabolismo , Nervo Vago/imunologia , Nervo Vago/metabolismoRESUMO
Hypertension and associated inflammatory processes that accelerate cardiovascular damage are regulated by the innate immune system. Toll-like receptors (TLR) are major components of the innate immune system that recognize endogenous damage-associated molecular patterns to activate prominent inflammatory signaling including activation of nuclear factor-κB (NF-κB). However, the role of TLR in the etiology of hypertension is not well understood. TLR signaling is dependent on adaptor proteins that, along with the TLR expression patterns, confer specificity of the inflammatory response and its pathological targets. Here we review the conceptual framework of how TLR and their adaptor proteins may differentially affect hypertension and cardiac hypertrophy by different stimuli.
Assuntos
Hipertensão/fisiopatologia , Imunidade Inata/fisiologia , Receptores Toll-Like/fisiologia , Animais , Cardiomegalia/fisiopatologia , Humanos , NF-kappa B/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Nine endosulfan degrading bacterial strains were isolated by soil enrichment with endosulfan. Bacterial strain M3 was the most efficient degrader. Endosulfan degradation was accompanied by a decrease in pH of the medium and an increase in chloride ion concentration. The bacterium was tested for its ability to degrade endosulfan at different concentrations in broth and soil. Maximum degradation occurred at concentrations of 50 µg/ml of broth and 100 µg/g of soil. Values of Ks and Vmax were different for (α)- and (ß)-endosulfan in broth. The kinetic indices (Vmax/Ks) for α-endosulfan and ß-endosulfan were 0.051 and 0.048 day(-1) respectively, indicating that (α)-endosulfan was more rapidly degraded. Bacterial strain M3 was identified as Klebsiella sp. M3 on the basis of 16S rDNA sequence similarity (GenBank accession number JX273762).
Assuntos
Endossulfano/metabolismo , Inseticidas/metabolismo , Klebsiella/metabolismo , Microbiologia do Solo , Poluentes do Solo/metabolismo , Biodegradação Ambiental , Solo/químicaRESUMO
Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2 , Transdução de Sinais , Receptores de Estrogênio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular TumoralRESUMO
Pierre Robin sequence poses a great challenge for anesthesiologists during laryngoscopy and intubation, making oxygenation and ventilation difficult. The role of early surgical intervention is recommended for the improvement of the airway and overall survival of the neonate. The situation becomes even more challenging, when the neonate may not be fit for such surgical interventions. The present case posed such a challenge to the team. To the authors' knowledge, the decision to use a face mask as an interim life-saving measure was considered for the first time. This provided a greater window of opportunity for further course of action, only to be later managed by distraction osteogenesis of the mandible. The unconventional use of orthopedic appliances for the management of threatened airways may provide the clinician with time, where further management may be carried out. The present article will explain such a procedure that was carried out as a life-saving measure.
RESUMO
Diabetes worsens the outcomes of a number of vascular disorders including peripheral arterial disease (PAD) at least in part through induction of chronic inflammation. However, in experimental PAD, recovery requires the nuclear factor-kappa B (NF-κB) activation. Previously we showed that individually, both ischemia and high glucose activate the canonical and non-canonical arms of the NF-κB pathway, but prolonged high glucose exposure specifically impairs ischemia-induced activation of the canonical NF-κB pathway through activation of protein kinase C beta (PKCß). Although a cascade of phosphorylation events propels the NF-κB signaling, little is known about the impact of hyperglycemia on the canonical and non-canonical NF-κB pathway signaling. Moreover, signal upstream of PKCß that lead to its activation in endothelial cells during hyperglycemia exposure have not been well defined. In this study, we used endothelial cells exposed to hyperglycemia and ischemia (HGI) and an array of approximately 250 antibodies to approximately 100 proteins and their phosphorylated forms to identify the NF-κB signaling pathway that is altered in ischemic EC that has been exposed to high glucose condition. Comparison of signals from hyperglycemic and ischemic cell lysates yielded a number of proteins whose phosphorylation was either increased or decreased under HGI conditions. Pathway analyses using bioinformatics tools implicated BLNK/BTK known for B cell antigen receptor (BCR)-coupled signaling. Inhibition of BLNK/BTK in endothelial cells by a specific pharmacological inhibitor terreic acid attenuated PKC activation and restored the IκBα degradation suggesting that these molecules play a critical role in hyperglycemic attenuation of the canonical NF-κB pathway. Thus, we have identified a potentially new component of the NF-κB pathway upstream of PKC in endothelial cells that contributes to the poor post ischemic adaptation during hyperglycemia.
RESUMO
The pharmaceutical industry has embraced the quality-by-design (QbD) approach as a promising development, formulation and manufacturing strategy. QbD provides a systematic and science-based framework for designing and producing high-quality products, with a particular focus on identifying, assessing and controlling risks throughout the development process. This review aims to assess the benefits of implementing QbD in pharmaceutical processes, evaluate its impact on regulatory compliance and explore its potential to enhance drug product quality. The primary objective of this review is to evaluate the influence of QbD on pharmaceutical development and manufacturing processes. It also seeks to examine the regulatory requirements associated with the implementation of QbD and highlight the advantages of this approach in terms of product quality and cost-effectiveness. Additionally, the review aims to explore the potential of QbD in improving the safety and efficacy of drug products. The QbD approach holds tremendous potential to revolutionize the pharmaceutical industry by optimizing drug development & manufacturing processes, reducing costs and enhancing product quality and consistency. However, implementing QbD requires a comprehensive understanding of the underlying science, as well as strict adherence to regulatory requirements in drug development and manufacturing. In conclusion, by embracing the QbD approach, the pharmaceutical industry can ensure the production of safe, effective and regulation-compliant products while simultaneously improving process efficiency. This strategic shift toward QbD represents a pivotal step in advancing pharmaceutical research and manufacturing capabilities, ultimately benefiting both the industry and more importantly, patients worldwide.
Assuntos
Indústria Farmacêutica , Humanos , Controle de Qualidade , Preparações FarmacêuticasRESUMO
Peripheral artery disease (PAD) is one of the major cardiovascular diseases that afflicts a large population worldwide. PAD results from occlusion of the peripheral arteries of the lower extremities. Although diabetes is a major risk factor for developing PAD, coexistence of PAD and diabetes poses significantly greater risk of developing critical limb threatening ischemia (CLTI) with poor prognosis for limb amputation and high mortality. Despite the prevalence of PAD, there are no effective therapeutic interventions as the molecular mechanism of how diabetes worsens PAD is not understood. With increasing cases of diabetes worldwide, the risk of complications in PAD have greatly increased. PAD and diabetes affect a complex web of multiple cellular, biochemical and molecular pathways. Therefore, it is important to understand the molecular components that can be targeted for therapeutic purposes. In this review, we describe some major developments in enhancing the understanding of the interactions of PAD and diabetes. We also provide results from our laboratory in this context.
RESUMO
Individuals with Autism Spectrum Disorder (ASD) often exhibit difficulty in movement preparation and allocating attention towards different Regions of Interest (ROIs) of a visual stimulus. Though research has alluded to differences in movement preparation for aiming tasks between individuals with ASD and typically developing (TD) individuals, there is limited evidence (true for near-aiming tasks) on the contribution of the window (i.e., time duration) of movement preparation (i.e., the planning window preceding movement initiation) on one's aiming performance. However, investigation of the contribution of this planning window on one's performance in far-aiming task remains as majorly unexplored. Again, often one's eye movement leads the initiation of hand movement (for task execution) indicating the importance of monitoring one's eye movement in the planning stage, critical for far-aiming task. Most of the studies (in conventional settings) examining the role of gaze behavior on aiming performance have involved TD individuals and only a few involving individuals with ASD. Here, we have designed Virtual Reality (VR)-based Gaze-sensitive far-aiming (dart throw) task and monitored the looking pattern of participants while they interacted with the task environment. We carried out a study with 40 participants (20 in each of ASD and TD groups) to understand how the participant groups differed in task performance and gaze fixation within the movement planning window. We observed difference in the scan path and last fixation within the movement planning window before triggering the release of the dart with relevance to task performance.