Faculty reviews最新文献

This review examines the role of circulating cell-free DNA (cfDNA) as potential drivers of inflammation and their potential application as mechanistic biomarkers in Inflammatory Bowel Diseases (IBD). These DNA fragments contain significant information about their origins, the underlying host pathology leading to their release, and possess properties that can fuel the inflammatory process. Recent advances in sequencing and analytical approaches have made the translation of cfDNA into clinical practice a promising prospect. We focus on the functional relevance of cfDNA in the inflammatory process and discuss its potential for future assessments of IBD activity and identification of therapeutic options.

This brief review focuses on two contentious issues within the field of non-alcoholic fatty liver disease (NAFLD); the first is the recent effort to redefine NAFLD as metabolic (dysfunction)-associated fatty liver disease (MAFLD). The modification of "NAFLD" to "MAFLD" is expected to highlight the role of metabolic factors in the disease aetiology, which is hoped to improve patient understanding of the disease, facilitate patient-physician communication and highlight the importance of public health interventions in prevention and management. The diagnostic criteria for MAFLD allow it to coexist with other forms of liver disease, which recognises that metabolic dysfunction contributes towards disease progression in other liver pathologies, such as alcoholic liver disease. However, there remain concerns that renaming NAFLD may be premature without fully considering the broader implications, from diagnostic criteria to trial endpoints; therefore, the new definition has not yet been accepted by major societies. Another contentious issue within the field is the gap in our understanding of how patients undergoing therapeutic interventions should be monitored to assess amelioration/attenuation or the worsening of their liver disease. Biomarker scoring systems (such as the ELF test and FIB-4 test) and imaging techniques (such as transient elastography [TE] and magnetic resonance imaging [MRI] techniques) are proven to be reasonably accurate, and comparable with histology, in the diagnosis of NAFLD and evaluation of disease severity; however, their use in monitoring the response of disease to therapeutic interventions is not well established. Whilst biomarker scoring systems and TE are limited by poor diagnostic accuracy in detecting moderate fibrosis (e.g. F2 liver fibrosis defined by histology), more accurate MRI techniques are not practical for routine patient follow-up due to their expense and limited availability. More work is required to determine the most appropriate method by which therapeutic interventions for NAFLD should be monitored in clinical practice.

Pituitary adenomas (PAs) are common intracranial tumors. Despite their benign nature, PAs may cause a significant burden of disease, leading to either hormonal disturbances or local compression. A subset of PAs presents an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. Therefore, early diagnosis and treatment are important. Advances in molecular pathology have improved the understanding of their pathogenesis and offer opportunities to identify and target novel pathways. Improved imaging and functional molecular techniques precisely detect even very small tumors and guide targeted treatment. Transsphenoidal surgery is the first-line treatment for the majority of PAs, and advances in the field of endoscopic neurosurgery offer excellent outcomes. Dopamine agonists (DAs) are traditionally the first-line treatment for prolactinomas. For patients with acromegaly, first- and second-generation somatostatin analogues (SSAs) are applied when surgery is not successful or not indicated. For Cushing's disease (CD), drugs targeting adrenal steroidogenesis, somatostatin receptors in the pituitary, and glucocorticoid receptors are used to treat hypercortisolism in patients with persistent or recurrent CD, for those who are not good surgical candidates, and as a bridge treatment for those who have undergone radiation treatment until cortisol levels are controlled. Temozolomide (TMZ) is the first-line chemotherapy for aggressive PAs, but new experimental therapies, like the anti-vascular endothelial growth factor (anti-VEGF) therapy, mechanistic target of rapamycin (mTOR) inhibitors, tyrosine kinase inhibitors, and cell cycle and checkpoint inhibitors, are now available. Radiotherapy is offered to patients with residual, recurrent, or progressive tumors. Modern techniques in radiotherapy planning and delivery are able to deliver high doses to the target tissue while sparing vital structures. As we familiarize ourselves with the biological behavior of PAs and our therapeutic armamentarium expands, the next goal is to tailor and personalize treatment to each individual patient so as to achieve the best outcome.

Endoscopic screening is premised on the detection of pre-symptomatic, early-stage gastric neoplasia that enables curative resection. Endoscopic screening reduces gastric cancer mortality in high-incidence countries but is highly resource-intensive. Endoscopic surveillance of high-risk subgroups of intestinal metaplasia has gained traction in low and intermediate-incidence countries, and emerging evidence suggests that risk-stratified endoscopic surveillance may facilitate timely detection of cancer. However, outcome-based evidence is required to support its adoption. Yet the impact of an endoscopy-based strategy may well lie in heralding a paradigm that regards every routine diagnostic gastroscopy as an opportunity to screen for GC. Endoscopic surveillance also renders gastric intestinal metaplasia a de facto disease, and the ramification of this needs to be further elucidated.

Postoperative delirium (POD) is a major public health problem associated with poor patient outcomes such as increased hospital lengths of stay, loss of functional independence, and higher mortality. Depending on the study, the reported incidence ranges from 5% to 65%, with the highest incidence in hip and cardiac surgery. Anesthesiologists should be familiar with the predisposing and precipitating factors of POD, particularly screening for preoperative cognitive impairment and frailty syndrome. Screening tools, for example, the Mini-Mental State Exam, Mini-Cog, 4 A's test for delirium screening, and Montreal Cognitive Assessment, can be used to assess for cognitive impairment and the Clinical Frailty Scale to assess for frailty syndrome. The Hospital Elder Life Program is the standard prevention protocol that is tried and tested in reducing the incidence of POD. Prehabilitation, lung protective strategies, pharmacologic agents such as ramelteon, a melatonin receptor agonist, glucocorticoids, dexmedetomidine, and non-pharmacologic agents, such as noise reduction strategies and the encouragement of nocturnal sleep, have all led to a decrease in the incidence of POD and are being studied for their efficacy. However, the data are inconclusive to date. Intraoperatively, preventing hypotension and blood pressure swings, ensuring adequate pain control and anesthetic depth, and using age-adjusted minimum alveolar concentration (MAC) titration reduce the incidence of POD. The incidence of POD using regional or general anesthesia is similar. In this narrative review, we will discuss the current understanding of the predictors, pathophysiology, prevention, and management of POD and identify areas of further research.

Gastric adenocarcinomas are a significant cause of cancer and cancer death, globally. The curative approach for those with diagnosed localized disease is with surgical resection and an adjunctive approach of perioperative chemotherapy, postoperative adjuvant therapy, or postoperative chemoradiation. Unfortunately, a universal standard approach is lacking for adjunctive therapy which in part has limited the progress achieved in this area. Metastatic disease is common in the Western world at diagnosis. Metastatic disease is treated palliatively with systemic therapy. Targeted therapy has stalled in approvals in gastric adenocarcinomas. Recently, we have seen the exploration of promising targets along with the addition of immune checkpoint inhibitors in select patients. Here, we review recent advances seen in gastric adenocarcinomas.

Acute and chronic graft-versus-host disease (GVHD) continue to present a significant challenge to physicians, accounting for considerable haematopoietic stem cell transplant (HSCT)-related morbidity and mortality, particularly those patients with steroid-refractory disease. In this review, we discuss recent advances in understanding the underlying pathophysiology, prevention and management of acute and chronic GVHD. Barriers to progress include the difficulty in obtaining high-quality evidence with sufficient patient numbers to identify optimal preventative and treatment strategies, with the heterogeneity of multiple patient, donor, graft and transplant-related factors, in addition to limited availability of human tissue to study the underlying pathophysiology, particularly in steroid-refractory disease. Continued collaborative efforts to improve our understanding of the pathophysiology involved, particularly in steroid-refractory disease, identification of biomarkers to permit risk stratification, and further well-designed randomised clinical trials are essential to help physicians determine optimal GVHD preventative and treatment strategies for each individual patient.

Ménière's disease (MD) is a rare syndromic disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. The phenotype is variable, and it may be associated with other comorbidities, such as migraine, asthma, and several autoimmune disorders. The condition has a significant heritability according to epidemiological and genetic data, with a difference in comorbidities according to ethnicity. Familial MD is found in 10%, the most commonly found genes being OTOG, MYO7A and TECTA, previously associated with autosomal dominant and recessive SNHL. These findings suggest that proteins involved in the tectorial membrane and stereocilia links are critical in the pathophysiology of MD. Moreover, proinflammatory cytokines may have a role in some patients with MD by promoting a persistent inflammatory status. Preliminary data suggest that sodium intake could be related to the release of cytokines, and this may influence the relapsing course of the condition. The ionic homeostasis of the otolithic and tectorial membranes could be critical in suppressing the innate motility of individual hair cell bundles, and focal detachment of the otolithic, or tectorial membranes may cause random depolarization of hair cells and explain changes in tinnitus loudness or the triggering of vertigo attacks.

The control of gene expression in eukaryotes relies on how transcription factors and RNA polymerases manipulate the structure of chromatin. These interactions are especially important in development as gene expression programs change. Chromatin generally limits the accessibility of DNA, and thus exposing sequences at regulatory elements is critical for gene expression. However, it is challenging to understand how transcription factors manipulate chromatin structure and the sequence of regulatory events. The Drosophila embryo has provided a powerful setting to directly observe the establishment and elaboration of chromatin features and experimentally test the causality of transcriptional events that are shared among many metazoans. The large embryo is tractable by live imaging, and a variety of well-developed tools allow the manipulation of factors during early development. The early embryo develops as a syncytium with rapid nuclear divisions and no zygotic transcription, with largely featureless chromatin. Thus, studies in this system have revealed the progression of genome activation triggered by pioneer factors that initiate DNA exposure at regulatory elements and the establishment of chromatin domains, including heterochromatin, the nucleolus, and nuclear bodies. The de novo emergence of nuclear structures in the early embryo reveals features of chromatin dynamics that are likely to be central to transcriptional regulation in all cells.

The 13th Federation of American Societies for Experimental Biology (FASEB) Summer Research Conference, "TGF-β superfamily signaling in development and disease" was convened at the Grand Hotel in Malahide, Ireland in July 2022. The Transforming Growth Factor-β (TGF-β) family of secreted proteins consists of agents of intercellular communication found in all multicellular animals. Attending the meeting was a diverse group of scholars with shared interests in understanding TGF-β signaling mechanisms, normal functions, and the diseases associated with misregulation and mutation. Despite intense study over the previous 35 years, new features of TGF-β activity continue to be discovered. This meeting report offers 21 investigator-provided summaries that illustrate the breadth of the thought-provoking presentations. An emerging theme of the meeting was the power of cross-disciplinary studies, such as one combining immunology, biochemistry, and structural biology, to unravel the secrets of parasitic TGF-β mimics. Please join us at the next meeting.