The role of the ThyGeNEXT oncogene panel used in combination with the expanded miRNA panel ThyraMIRv2 in Indeterminate thyroid nodules: A large, blinded, real-world, observational study.

BACKGROUND: Molecular analysis of fine-needle aspiration biopsies (FNAB) improves the diagnostic accuracy of cytologically indeterminate thyroid nodules (ITNs). Recently, the use of MPTXv2 has been shown to further improve the accuracy of risk stratification of ITNs. METHODS: A total of 338 patient samples with atypia of undetermined significance (n = 260) or follicular neoplasm (n = 78) cytology diagnosis and corresponding surgical outcomes or clinical follow-up, collected between 2016 and 2020 were included. All samples underwent multiplatform testing (MPTXv1), which includes an oncogene panel (ThyGeNEXT®) plus a microRNA risk classifier (ThyraMIR®). A blinded, secondary analysis was performed to assess the added utility of MPTXv2 (ThyraMIR®v2). The average length of follow-up for the surveillance group (n = 248) was 30 months. RESULTS: Sensitivity at moderate threshold was 96% and specificity at positive threshold was 99% for MPTXv2. At 14% disease prevalence, the negative predictive value at the moderate threshold was 99% and the positive predictive value at the positive threshold was 89% for MPTXv2. MPTXv2 had fewer patients classified into the moderate-risk group than MPTXv1, which was statistically significant (p < .001). Using surgical resection, the gold standard for outcomes, MPTXv2 showed a statistically greater area under the curve (p = .028) than MPTXv1, demonstrating greater accuracy for MPTXv2. CONCLUSION: Both test versions demonstrated robust performance with low false-positive molecular results. Data suggest that incorporation of MPTXv1, and more recently MPTXv2, into clinical practice within our healthcare network resulted in improved accuracy of ITN risk stratification.

Untangling Alzheimer's disease with spatial multi-omics: a brief review.

Alzheimer's disease (AD) is the most common form of neurological dementia, specified by extracellular ß-amyloid plaque deposition, neurofibrillary tangles, and cognitive impairment. AD-associated pathologies like cerebral amyloid angiopathy (CAA) are also affiliated with cognitive impairment and have overlapping molecular drivers, including amyloid buildup. Discerning the complexity of these neurological disorders remains a significant challenge, and the spatiomolecular relationships between pathogenic features of AD and AD-associated pathologies remain poorly understood. This review highlights recent developments in spatial omics, including profiling and molecular imaging methods, and how they are applied to AD. These emerging technologies aim to characterize the relationship between how specific cell types and tissue features are organized in combination with mapping molecular distributions to provide a systems biology view of the tissue microenvironment around these neuropathologies. As spatial omics methods achieve greater resolution and improved molecular coverage, they are enabling deeper characterization of the molecular drivers of AD, leading to new possibilities for the prediction, diagnosis, and mitigation of this debilitating disease.

Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1.

Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.

Atypical presentation of anti-HMGCR myopathy.

Immune-mediated necrotising myopathy is a subtype of idiopathic inflammatory myopathy characterised by muscle fibre necrosis without significant inflammatory infiltrate. Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) myopathy is seen in 6%-10% of idiopathic inflammatory myopathy and is diagnosed in the context of elevated serum creatine kinase levels, proximal muscle weakness and anti-HMGCR autoantibodies. We recently encountered a 61-year-old man with anti-HMGCR myopathy with an atypical skin manifestation, partially responsive to triple therapy with steroids, intravenous immunoglobulin (IVIG) and rituximab. To our knowledge, there have been only four reported cases of skin rash associated with anti-HMGCR myopathy. Our case demonstrates the importance of recognising atypical manifestations of anti-HMGCR myopathy. Early addition of IVIG and rituximab is also critical in patients not responding to steroid monotherapy. Delay in achieving remission leads to prolonged steroid use, lower likelihood of beginning physical therapy and overall worse clinical outcomes.

Challenges in Treating Statin-Associated Necrotizing Myopathy.

Myalgia and mild elevation in muscle enzymes are common side effects of statin therapy. While these symptoms are generally self-limited, in rare cases, statin use is associated with an immune-mediated necrotizing myopathy caused by development of autoantibodies against HMG-CoA reductase. The primary presenting symptom of this condition is progressive symmetric proximal weakness that does not abate or worsens even after cessation of statin therapy and is associated with markedly elevated creatine kinase (CK) levels. To date, no randomized controlled trials have been conducted to identify the most effective treatment for statin-associated autoimmune myopathy. Treatment recommendations involve a combination of steroids and immunosuppressive drugs. This single-center case series highlights the clinicopathologic features diagnostic for statin-associated autoimmune myopathy as well as treatment challenges for the patient population. The series highlights a range of potential presentations, from mildly symptomatic despite highly elevated CK, to severe muscle weakness including dysphagia. Multiple patients required several immunosuppressant medications as well as intravenous immunoglobulin (IVIG) to achieve disease control. In this case series, marked improvement was noted in several diabetic patients with IVIG.

Disseminated Herpes Simplex Virus in an Immunocompetent Patient Without Presence of Epidermal or Mucosal Lesions.

ABSTRACT: Herpes simplex virus (HSV) is a disease usually characterized by lesions within the epidermis or mucosa of children and adults. However, this infection can also cause complications to many systems of the body, including the peripheral and central nervous system, respiratory system, and hepatobiliary system. In this case, we present a 43-year-old man with a history of substance abuse, who presented with fever, cough, and headache, and within days, progressed into fulminant hepatitis and hypoxic failure. Bacterial and fungal cultures were negative, as well as the workup for human immunodeficiency virus. However, the presence of HSV was detected in a bronchial lavage culture after the patients had expired. This result, along with the findings at autopsy, including viral cytopathic effect in the lung and liver, which were confirmed with immunohistochemical stains for HSV, strongly suggest that the cause of death is from disseminated herpes virus infection with hepatitis and viral pneumonitis. This disseminated infection occurred in an immunocompetent host without any evidence of mucocutaneous lesions.