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Nutritional Diseases
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Chelsea Kesty, Madeline Hooper, Erin McClure, Emily Chea, Cynthia Bartus
Overview: Zinc deficiency is most prevalent in sub-Saharan Africa and South Asia while relatively rare in North America. Groups most at risk for zinc deficiency include pregnant and lactating women due to increased zinc demand, as well as vegetarians, alcoholics, and people with digestive disorders (e.g., Crohn’s disease and ulcerative colitis) due to decreased absorption or parenteral feeding. Acrodermatitis enteropathica is an inherited or acquired disorder associated with zinc deficiency and is characterized by periacral and periorificial dermatitis, alopecia, and diarrhea. Primary acrodermatitis enteropathica is an autosomal recessive disorder caused by a loss-of-function mutation of the SLC39A4 gene located on chromosome 8q24.3, which codes for the zinc transporter protein ZIP4. This mutation results in a decrease in zinc absorption across the mucosa of the small intestine.
Answers
Published in Samar Razaq, Difficult Cases in Primary Care, 2021
Acrodermatitis enteropathica is a rare genetic disease inherited in an autosomal recessive pattern. It is likely that gene mutations result in a defective zinc transporter protein, resulting in reduced uptake from the intestine. This may become apparent when the child is weaned off breast milk, because of low bioavailability of zinc in alternative milk sources and solids. Zinc deficiency may also be acquired in other conditions that cause malabsorption, such as cystic fibrosis. The rash is erythematous and crusted and may be well demarcated from normal skin. The rash can affect the eyes, mouth and nose, tips of fingers, knees and elbows. Hair loss may occur and wound healing can be impaired. Superimposed bacterial and candidal infection may also occur. The genetic form requires lifelong zinc replacement, which results in rapid improvement in the child. Papular acrodermatitis of childhood is a papular eruption affecting the extremities, associated with anicteric hepatitis (raised alanine aminotransferase, normal bilirubin levels). It is thought to be of viral aetiology, with hepatitis B virus particularly implicated.
Sudden unexpected death in epilepsy
Published in Helen Whitwell, Christopher Milroy, Daniel du Plessis, Forensic Neuropathology, 2021
Christopher Milroy, Daniel du Plessis
There is no single neuropathological feature that can categorically confirm that seizures occurred during life, although some patterns of original neuronal damage and reorganisation such as mossy fibre sprouting are relatively specific for seizure-related brain injury over time. Alterations in the granule cell composition/distribution in the dentate gyrus (such as dispersion or broadening of the granule cell layer) and reorganisation or sprouting of axons in the granule cells (mossy fibres, readily demonstrated by immunohistochemistry, including zinc transporter protein 3 [Figure 13.2]) can aid in the distinction of hippocampal damage due to epilepsy from other causes of the hippocampal neuronal loss such as due to hypoxic-ischaemic injury and neurodegenerative disease (Thom 2019). There is no evidence that hippocampal sclerosis is more common in SUDEP nor evidence of increased inflammation, including lymphocyte-mediated inflammation and microglial activation in SUDEP, compared to control groups. Acute neuronal injury seen as eosinophilic neuronal change is reported in approximately half of the cases of SUDEP subject to a post-mortem. The demonstration of neuronal HSP-70, HIF-1α and c-jun expression can be seen in such neurons in the CA1/subiculum region. Whilst such evidence of acute neuronal injury could reflect recent seizure-related neuronal hippocampal injury, similar changes could be explained by hypoxic-ischaemic events and/or excitotoxic cellular stresses and it can therefore not be regarded as reliable evidence of recent seizure activity (Thom 2019).
Triple-negative breast cancer: promising prognostic biomarkers currently in development
Published in Expert Review of Anticancer Therapy, 2021
Jasmine Sukumar, Kelly Gast, Dionisia Quiroga, Maryam Lustberg, Nicole Williams
Trop-2 is a type I transmembrane glycoprotein, with a relevant role in migration, cell proliferation, cell cycle progression, and metastasis [117]. Sacituzumab govitecan (IMMU-132) is an antibody targeting Trop-2, linked to the topoisomerase-I inhibitor SN-38, the active metabolite of irinotecan that induces DNA damage [120]. IMMU-132-01 (NCT01631552), a phase I/II clinical trial, showed the efficacy of Sacituzumab Govitecan-hziy, with 33.3% response rate in heavily pretreated TNBC patients. Based on these results, on 22 April 2020, the FDA granted accelerated approval to Sacituzumab Govitecan-hziy for patients with metastatic TNBC who received at least two prior therapies for metastatic disease [120]. GPNMB is involved in processes like cell migration, invasion, angiogenesis, or epithelial-mesenchymal transition, highly overexpressed in TNBC, and a biomarker of poor prognosis in BC [118]. LIV-1 is a zinc transporter protein downstream target of STAT3, implicated in cell adhesion and epithelial-to-mesenchymal transition [119]. CA6 is selectively expressed on solid tumors, and is therefore, an ideal target for ADC therapy. Additional ADCs are currently under investigation such as, SAR566658 which is an ADC directed against CA6 which carries DM4, a maytansine-derived anti-microtubule agent, as payload (NCT01156870).
The dawn of targeted therapies for triple negative breast cancer (TNBC): a snapshot of investigational drugs in phase I and II trials
Published in Expert Opinion on Investigational Drugs, 2020
My-my Huynh, Mary Rose Pambid, Aarthi Jayanthan, Andrew Dorr, Gerrit Los, Sandra E. Dunn
Ladiratuzumab vedotin (SGN-LIV1A) is an ADC that links a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) to the LIV-1-targeted monoclonal antibody. LIV-1, a zinc transporter protein with metalloproteinase activity that plays a role in epithelial-to-mesenchymal transition, is expressed in 65% of cases of TNBC compared to limited expression in normal breast tissue [47]. The safety and tolerability of SGN-LIV1A is being investigated in heavily pre-treated MBC patients in an ongoing phase I trial (NCT01969643), however only a subset of the patients have TNBC. Another ongoing phase Ib/II clinical trial (NCT03310957) with SGN-LIV1A is testing a combination with pembrolizumab as 1 L therapy. In an early 3-month follow up of 26 patients, promising results have emerged with a confirmed ORR of 54% in patients dosed with a combination of SGN-LIV1A and pembrolizumab [48]. However, treatment emergent AEs occurred in 86% of the patients evaluable for safety and the most common AEs included nausea (53%), fatigue (45%) and diarrhea (43%). In addition, the most common grade 3 AE was neutropenia (16%).
Clinical development of antibody-drug conjugates in triple negative breast cancer: can we jump higher?
Published in Expert Opinion on Investigational Drugs, 2022
LIV-1, alternatively known as ZIP6, a breast cancer associated zinc transporter protein, was initially identified as an estrogen-induced gene in a breast cancer cell line [49]. Functionally, it was found to be a mediator of EMT (epithelial-to-mesenchymal transition) in zebrafish gastrulation through STAT3 (signal transducer and activator of transcription 3) signaling [50]. Studies conducted in breast and prostate tumor models indicated similar findings, with LIV-1 mediating EMT, as well as supporting tumor cell motility and metastatic dissemination, thus rendering LIV-1 a potential therapeutic target for patients with cancer [51–53].