Aims: Sporadic renal cell carcinomas with fibromyomatous stroma (RCC FMS) with coexistent haemangioblastoma (HB)‐like morphology have been previously reported. Such morphology has not, however, been documented in patients with tuberous sclerosis complex (TSC). We evaluated clinicopathologic, immunohistochemical and molecular findings of RCC FMS with HB‐like features in three TSC patients.Methods and results: All three patients were females with confirmed germline mutations in TSC1 in the absence of VHL or other alterations. One patient had bilateral nephrectomy with six separate tumours (three in each kidney), and two patients had one tumour each, resected by partial nephrectomy. Prominent fibromuscular stroma was present at the tumoral periphery and surrounding clear cell nests forming tubules and papillary formations (RCC FMS areas), admixed with solid, clear to eosinophilic and spindle cell areas (HB‐like areas). HB‐like areas were variably represented in individual tumours, but in some, HB‐like features were almost exclusive. HB‐like areas were negative for CK7 and showed inhibin‐α and S100 reactivity, in contrast to typical RCC FMS areas, which were CK7 positive, while negative for inhibin‐α and S100. GPNMB, which is consistently expressed in TSC/mTOR altered tumours, was positive in both components. On follow‐up (10 months–21 years), all patients had an indolent course.Conclusions: HB‐like morphology found in RCC FMS in TSC patients represents part of the morphologic spectrum of RCC FMS, which is a previously underreported and underrecognized feature. RCC FMS with HB‐like areas show uniform GPNMB reactivity and are associated with TSC/MTOR alterations, but not with VHL alterations.

Calcium (Ca²⁺) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca²⁺, resulting in the propagation of Ca²⁺ signals through the activation of processes, such as store-operated Ca²⁺ entry (SOCE). SOCE provides a sustained Ca²⁺ entry into the cytosol; moreover, the uptake of SOCE-mediated Ca²⁺ by mitochondria can shape cytosolic Ca²⁺ signals, function as a feedback signal for the SOCE molecular machinery, and drive numerous mitochondrial processes, including adenosine triphosphate (ATP) production and distinct cell death pathways. In recent years, tremendous progress has been made in identifying the proteins mediating these signaling pathways and elucidating molecular structures, invaluable for understanding the underlying mechanisms of function. Nevertheless, there remains a disconnect between using this accumulating protein structural knowledge and the design of new research tools and therapies. In this review, we provide an overview of the Ca²⁺ signaling pathways that are involved in mediating S/ER stored Ca²⁺ release, SOCE, and mitochondrial Ca²⁺ uptake, as well as pinpoint multiple levels of crosstalk between these pathways. Further, we highlight the significant protein structures elucidated in recent years controlling these Ca²⁺ signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design.

The emergence of new-onset neuropsychiatric symptoms in middle age presents a diagnostic challenge, particularly when differentiating between a primary psychiatric disorder and an early neurodegenerative disease. The discrepancy between bedside clinical diagnosis and subsequent neuropathological findings in such cases further highlights the difficulty of accurately predicting pathology, especially when there are no evident focal lesions or changes in brain volume. Here we present the case of a 59-year-old woman with inconclusive neuroimaging who exhibited pronounced neuropsychiatric and behavioral symptoms initially suggestive of a mood disorder, then of behavioral variant frontotemporal dementia. However, upon autopsy, we identified coexisting Lewy body disease pathology and tau-related changes, including argyrophilic grain disease and primary age–related tauopathy. This case illustrates the challenges encountered when diagnosing late-onset neuropsychiatric symptoms, emphasizes the link between such symptoms and early-onset dementia and argyrophilic grain disease, and contributes to our understanding of the impact of mixed neuropathology in this population. Accurate diagnosis is essential for the development of molecular-specific therapies and, as well as for accurate prognosis and enrollment in clinical trials.

Background and ObjectivesAdult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP) causes a progressive neurodegenerative disease, with typical onset in the fourth decade of life. ...