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Advances in lower extremity peripheral nerve surgery
No full textPeripheral nerve injury (PNI) is a common source of pain and disability in patients. While many patients are affected by PNI, peripheral nerve surgery advancements in the lower extremity have lagged behind the upper extremity. Subsequently, principles that have demonstrated success in the upper extremity have been implemented in the lower extremity. Interventions with recent advances include the advent of novel nerve transfers in the lower extremity and using stem cells and electrical stimulation (ES) for nerve regeneration. This article focuses on advances in nerve transfers for lower extremity PNI and provides details on the basic science and clinical applications of newer interventions
Two rare cancers of the exocrine pancreas: to treat or not to treat like ductal adenocarcinoma?
No full textPancreatic cancer is an aggressive malignancy with increasing incidence. Pancreatic ductal adenocarcinoma (PDAC) accounts for > 90% of pancreatic cancer diagnoses, while other exocrine tumors are much rarer. In this review, we have focused on two rare cancers of the exocrine pancreas: adenosquamous carcinoma of the pancreas (ASCP) and pancreatic acinar cell carcinoma (PACC). The latest findings regarding their cellular and molecular pathology, clinical characteristics, prognosis, and clinical management are discussed. New genetic and transcriptomic data suggest that ASCP is related to or overlaps with the basal transcriptomic subtype of PDAC. These tumors are highly aggressive and driven by activated KRAS and MYC expression. Clinical outcomes remain poor and effective treatments are limited. PACC has no morphologic or genetic resemblance to PDAC and more favorable outcomes. Early stage PACC patients have improved survival with surgical resection and patients with advanced disease benefit most from platinum- or fluoropyrimidine-containing chemotherapy. Frequency of actionable genetic mutations is high in this disease and case reports suggest good outcomes when matched therapy is given. Dedicated clinical studies examining ASCP and PACC are limited and difficult to accrue. Further research is needed to define optimal clinical management for these rare diseases
Liver Transplantation for perihilar cholangiocarcinoma. Do we need to move forward?
No full textPerihilar cholangiocarcinoma (pCCA) is a challenging disease with limited options. Surgical resection and adjuvant therapy remain the only established treatment for those with resectable disease. Since the publication of the Mayo protocol in 2000, neoadjuvant chemoradiation and liver transplantation have become the standard of care in selected patients with unresectable de novo pCCA or resectable pCCA arising under primary sclerosing cholangitis. However, its application is diverse worldwide, and the need for donor organs is one of the main limitations. Also, differences in the neoadjuvant regimen used were observed. In this review, we discuss the latest results of this approach, the recommended tools for diagnostic work-up, and advances in systemic therapy to improve patient selection and long-term survival
Anti-BCMA novel therapies for multiple myeloma
No full textRecent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals; however, the prognosis remains poor. The BCMA antigen is highly expressed in myeloma cells, thus representing a target for novel therapies. Several agents that target BCMA through different mechanisms, including bispecific T cell engagers drug conjugated to antibody and CAR-T cells, are now available or under development. Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy. This review will discuss the recent development of anti-BCMA targeted treatments in myeloma, with a special focus on currently available agents
Hijacking intercellular trafficking for the spread of protein aggregates in neurodegenerative diseases: a focus on tunneling nanotubes (TNTs)
No full textOver the years, the influence of secretory mechanisms on intercellular communication has been extensively studied. In the central nervous system (CNS), both trans-synaptic (neurotransmitter-based) and long-distance (extracellular vesicles-based) communications regulate activities and homeostasis. In less than a couple of decades, however, there has been a major paradigm shift in our understanding of intercellular communication. Increasing evidence suggests that besides secretory mechanisms (via extracellular vesicles), several cells are capable of establishing long-distance communication routes referred to as Tunneling Nanotubes (TNTs). TNTs are membranous bridges classically supported by F-Actin filaments, allowing for the exchange of different types of intracellular components between the connected cells, ranging from ions and organelles to pathogens and toxic protein aggregates. The roles of TNTs in pathological spreading of several neurodegenerative conditions such as Prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) have been well established. However, the fragile nature of these structures and lack of specific biomarkers raised some skepticism regarding their existence. In this review, we will first place TNTs within the spectrum of intercellular communication mechanisms before discussing their known and hypothesized biological relevance in vitro and in vivo in physiological and neurodegenerative contexts. Finally, we discuss the challenges and promising prospects in the field of TNT studies
WHO’s latest rabies recommendations and guidance save lives and reduce the cost of treatment
No full textRabies vaccination is a crucial part of rabies post-exposure prophylaxis (PEP), but it tends to consist of long and costly regimens of intramuscular (IM) injections. Most human rabies deaths are caused by delayed access, unaffordability or ineffective delivery of PEP. Reducing these barriers is crucial to ensure that this incurable yet preventable disease does not cost lives. In 2022, WHO published new guidance towards the introduction or expansion of rabies vaccination into national immunization programmes to systematically drive down human rabies deaths effectively and cost-efficiently. Such guidance grounds on the latest scientific recommendation provided by WHO’s Strategic Advisory Group of Experts in 2018. WHO recommends a shortened 1-week rabies vaccination schedule, with visits on days 0, 3 and 7. On each visit, a 2-site intradermal (ID) injection (using only 0.1 ml of vaccine in each site) is administered. ID administration allows for vials to be shared among several patients within a 6-8 hours timeline. Compared to IM administration, ID is cost- and dose-sparing, even in low-throughput clinics. Additionally, this regimen requires only 3 visits to the healthcare facility, improving patient compliance. However, the uptake of this shortened ID regimen remains limited. It should now be a matter of urgency for Health Ministries in rabies-endemic settings to adopt the WHO-recommended shortened ID vaccination schedule and ensure appropriate medical training to improve PEP delivery. This will enable countries to improve PEP delivery and allow underserved populations to access affordable, life-saving rabies vaccines
Metabolic primary liver cancer in adults: risk factors and pathogenic mechanisms
No full textPrimary liver cancer (PLC) is a heterogeneous group of disorders arising with the background of chronic liver disease (CLD) owing to varying etiologies. PLC carries a high lethality rate and a substantial epidemiological, clinical, and financial burden, which is projected to escalate. The two most common PLC histotypes in adults are hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); the latter is sub-classified as either intrahepatic CC or extrahepatic CC. Over recent decades, there has been a decline of viral CLD accompanied by an increase in dysmetabolic CLD, resulting in PLC becoming relatively more common in Western countries. Metabolic co-morbidities are risk factors and co-factors for HCC and (increasingly) CC. Complex immunological, cellular, pro-inflammatory, molecular, and genetic processes in the systemic dysmetabolic milieu increase PLC risk. Improved understanding of these mechanisms requires close surveillance and early diagnosis of at-risk patients while paving the way for personalized medicine, chemoprevention, and innovative management of metabolic PLC
Cathepsin K: both a likely biomarker and a new therapeutic target in lymphangioleiomyomatosis?
No full textLymphangioleiomyomatosis (LAM) is a rare disease that is characterized by cystic lung destruction and lymphangiomas and is associated with a high risk of osteoporosis-related bone fractures. Its diagnosis is based on pulmonary anatomopathological criteria combined with chest computed tomography. VEGF-D is the only serum diagnostic biomarker used in the clinic, while inhibition of the mTOR pathway by rapamycin is currently the only reference therapy for LAM. Human cathepsin K (CatK), a potent collagenase predominantly found in osteoclasts, is considered as a valuable target for anti-osteoporosis and bone cancer therapy. Recently, CatK, which is overexpressed in lung cysts, was proposed as a putative LAM biomarker. Moreover, CatK may take part in the LAM pathophysiology by participating in pulmonary cystic destruction and bone degradation. Accordingly, targeting collagenolytic activity of CatK by exosite-binding inhibitors in combination with mTOR inhibition could represent an innovative therapeutic option for reducing lung destruction in LAM
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