Abstract Endoplasmic reticulum stress activates the unfolded protein response (UPR), a pathway linked to breast cancer (BC) progression, chemoresistance, and the formation of polyploid giant cancer cells (PGCCs). In a preliminary study, we identified a small subpopulation of breast cancer cells that were strongly positive for the phospho-PERK antibody in immunohistochemistry (IHC), some of which showed atypical mitosis and PGCC-like morphology. Because PGCCs are associated with tumor aggressiveness and poor outcomes, we hypothesize that the strongly PERK-positive BC cells represent PGCCs or their precursors and are enriched in tumors with active unfolded protein response (UPR) signaling. This study aimed to define the frequency of PERK-positive BC cells in BC, assess their association with UPR activation, and identify transcriptomic and proteomic features linked to tumors containing these cells. FFPE tissues from 131 BC patients (96 TNBC, 35 non-TNBC) were analyzed by IHC using antibodies against phospho-PERK, ATF6, and phospho-IRE1. All samples were collected before treatment. PERK-positive BC cells were defined as tumor cells with strong (3+) cytoplasmic and nuclear phospho-PERK staining. The IHC indicates an association between PERK-positive BC cells and tumors with a TNBC phenotype. These cells represent an heterogeneous population with broad variation in cell morphology and size, and mitosis status. Based on IHC results, 21 tumors (13 TNBC, 8 non-TNBC) were selected for nCounter multiomics, using BC360 and MO protein panel for transcriptomic and proteomic analysis, respectively. Eleven tumors contained abundant PERK-positive BC cells, while ten had few or none. Three normal breast tissues were included as controls. When breast cancer tumors with abundant PERK-positive BC cells were compared with those without, 388 genes were differentially expressed (p-value threshold 0.05), of which 296 had p-values < 0.01. Of them, SLPI, S100A7, SERPINB5, KIT, and PHGDH showed the most significant increase in expression (log fold-change >2.0), while 132 genes, including TFF1, PIP, TFF3, CDCA8, PAX5, IL24, and VEGFD, showed the most significant decrease in expression (log fold-change <-2.0). When BC tumors with abundant PERK+ cells were compared with normal breast tissue, 315 genes were differentially expressed (p-value threshold 0.05), of which 184 had p-values < 0.01. Of them, 28, including SPP1, KIFC1, CDK1, TOP2A, RRM2, CENPF, and MYBL2 had a log fold-change >2.0, while 94 genes, including APOD, ZBTB16, PDK4, RELN, TFF3, TIMP4, EGF, and VEGFD had a log fold-change <-2.0. Tumors containing abundant PERK-positive BC cells show clear evidence of unfolded protein response activation and a transcriptomic profile associated with aggressive behavior, metabolic reprogramming, and loss of differentiation. This study was funded by a grant from the Breast Cancer Research Foundation of Alabama (BCRFA) to LPY. Citation Format: LUIS DEL POZO-YAUNER, Veronica Ramirez-Alcantara, Elba A. Turbat-Herrera, Hector Chavarria Bernal, Maha Babker, Huseyin Kilic, Rosetta Campbell, Bahaaeldin Youssef, Ajay Singh, Julio Isael Perez-Carreon, Wei Yang, Guillermo A. Herrera. Characterization of PERK-positive polyploid-like breast cancer cells and their association with unfolded protein response signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7311.

Distal renal tubular acidosis (dRTA) is a rare but recognized renal complication of Sjögren's syndrome (SS), often resulting from autoimmune-mediated damage to acid-base transporters in the distal nephron. It commonly presents with electrolyte abnormalities including hypokalemia and metabolic acidosis. A 47-year-old woman with chronic kidney disease presented with recurrent hypokalemia, mild proteinuria, and sicca symptoms. Workup revealed non-anion gap metabolic acidosis, a positive urine anion gap, and renal potassium wasting consistent with dRTA. Autoimmune testing showed a high-titer ANA (1:1280) and elevated SSA (>8.0), confirming SS. Renal biopsy revealed mild interstitial fibrosis and glomerulosclerosis without evidence of tubulointerstitial nephritis or immune complex deposition. This finding supports prior evidence that SS-associated dRTA may occur secondary to functional tubular defects involving distal nephron transporters, even in the absence of overt inflammatory histologic changes. Acid-base disturbances improved with potassium and bicarbonate supplementation. This case highlights that significant tubular dysfunction in SS may occur despite minimal or absent histologic evidence of tubulointerstitial nephritis. dRTA in SS may result from autoimmune targeting of distal nephron transporters such as H⁺-ATPase and anion exchanger 1. Early recognition and supportive treatment are essential to prevent complications including nephrolithiasis, progressive kidney dysfunction, and life-threatening hypokalemia. SS should be considered in patients presenting with unexplained dRTA, and timely correction of electrolyte abnormalities is critical to optimizing outcomes.

The future of organ-based therapies in monoclonal light chain-associated renal diseases is centered on the utilization of techniques that can identify specific targets to inhibit initiation and/or control progression. The present study of renal biopsies of patients with light chain deposition disease in different stages of glomerular involvement using spatial transcriptomics revealed unique gene expressions and activation of cellular pathways in mesangial cells responsible for the initiation and progression of the disease processes that can be targeted pharmacologically. Among the over-expressed genes were RPL41, RPS26, ACTA2-actin protein, TNC, and TGF (transforming growth factor) β1. The RPS and RPL genes regulate ribosomal function, their increase resulting in accentuated production of proteins. TGF-β drives matrix formation by mesangial cells, TNC is the gene responsible for the tenascin-rich mesangial nodules, and ACTA2 is an actin protein gene in myofibroblastic cells (phenotypically transformed mesangial cells), resulting in increased and cytoplasmic relocalization of actin in mesangial cells, leading to surface ruffling to promote interactions of monoclonal light chains with the SORL1 receptor. The pathways activated included the eukaryotic translation initiator, the extracellular matrix/proteoglycans and organization, and the TGF-β1 signaling, all aimed at increasing the extracellular matrix in the mesangium, responsible for its nodularity. The genes and cellular pathways differed in the various stages of glomerular LCDD, emphasizing the need for designing personalized therapies based on the evaluation of renal biopsies. Additional laboratory testing using existing models of LCDDs should be utilized to prove the efficacy of the proposed targeted interventions.

The prognosis of myeloma is based on controlling the plasma cell burden and thus, management of the production of monoclonal light chains has improved considerably, expanding survival and quality of life. However, the effects of the monoclonal light chains in the various organs result in alterations that may lead to renal failure. There is a crucial need to ameliorate or abolish renal damage. Organ-based therapies must be developed. Glomerulopathic light chains interact with mesangial cells using the SORL1 receptor and downstream effects lead to divergent mesangial alterations. While the multi-step process occurring when amyloidogenic light chains interact with mesangial cells has been elucidated in the laboratory, gene expression profiles and activated cellular pathways in human glomeruli have not been probed. Mesangial cells from five renal biopsies at different stages of glomerular amyloidosis were interrogated using spatial transcriptomics and compared with those from normal biopsy controls to identify cellular pathways and gene expression changes. The two most significant statistically overexpressed genes (FDR <0.05) when comparing control, early vs late cases were heat shock protein 90AB1 and HSPB1, known to be involved in protein misfolding and aggregation. The overexpressed genes exercise function and regulation over cellular pathways promoting apoptosis, vesicular transport, metalloproteinase activation, collagen degradation, gap junction degradation, GTPase cycle activation, and organelle biogenesis. This data confirmed the results previously reached in the research laboratory. Spatial transcriptomics demonstrated uniquely activated genes and cellular pathways in mesangial cells involved in the initiation and progression of glomerular amyloidosis, uncovering novel genes and new therapeutic targets.

Primary renal neuroendocrine tumors are very rare neoplasms compared to neuroendocrine tumors from other anatomic locations, such as the thoracic and gastrointestinal tract regions. Typically, renal neuroendocrine tumors are well-differentiated, carry a good prognosis, are often larger at presentation than neuroendocrine tumors found at other anatomic locations, and lack the clinical manifestations characteristic of neuroendocrine tumors found at other anatomic sites. Due to the rarity of these tumors, their origins, behavior, and molecular-genetic features are yet poorly defined. Here we describe a case of a well-differentiated primary renal tumor in a 55-year-old woman.

Neurocristic cutaneous hamartoma (NCH) is a rare, benign neoplastic skin lesion characterized by a combination of neuroectodermal and mesodermal components. Clinically, NCH typically presents as asymptomatic, well-circumscribed, and elevated cutaneous nodules. Histopathologically, it is characterized by nests of pigmented melanocytes and varying degrees of fibrosis and collagen deposition. The precise etiology of NCH remains undetermined; however, it is hypothesized to arise from the aberrant development of neuromesenchyme. Due to its potential to mimic other pigmented melanocytic disorders, accurate differential diagnosis is crucial to prevent mismanagement. Surgical excision is the preferred treatment modality, offering a generally favorable prognosis and low recurrence rate. Conversely, malignant cutaneous neurocristic hamartoma (MCNH), an exceedingly rare malignant variant of NCH, poses a significantly different clinical challenge. This review focuses on the diagnostic criteria, clinical presentation, and management strategies for MCNH, emphasizing the need for differentiation from other similar cutaneous lesions. We present a detailed case report of MCNH in a 56-year-old female, highlighting its histopathological and immunohistochemical features to provide insights into the diagnosis and therapeutic approach for this exceptionally rare malignancy.

Metastatic disease to the breast is a rare event, accounting for 0.5-2% of all breast cancers. Outside of metastases from the contralateral breast, malignant ovarian epithelial tumors are the most common origin of these metastases. Here, we present a very rare case of a high-grade ovarian serous adenocarcinoma presenting clinically as inflammatory breast cancer in a 70-year-old woman.

Perry syndrome (PS) is a rare autosomal dominant disease characterized by parkinsonism, central hypoventilation, weight loss and depression and is caused by pathogenic mutations in the dynactin subunit 1 (DCTN1) gene (encoding p150glued protein). To date, only two cases have been reported in Latin America, specifically in Colombia and Argentina. The present study, to the best of our knowledge, reports the first recorded Mexican family with PS. The clinical features of the proband and a family history of early parkinsonism led to the suspicion of PS. The pathogenic variant NM_004082:c.212G>A, causing a (p.Gly71Glu) mutation in the p150glued protein, was identified in exon 2 of the DCTN1 gene by exome sequencing, confirming the diagnosis of PS. (p.Gly71Glu) has been previously identified in at least 4 cases of PS from different ethnic backgrounds. Genetic counseling was provided to the available family members. To clarify the impact of the (p.Gly71Glu) variant on the structure and function of the cytoskeleton-associated protein Gly rich (CAP-Gly) domain of p150glued, Glu71 mutated CAP-Gly domains were modeled and compared with the wild-type. It was hypothesized that the larger and more charged side chain of Glu may induce conformational and electrostatic changes, imposing a conformational restriction on the peptide backbone that would affect interaction with the p150glued protein partners, causing dysfunction in the dynactin protein complex.

Se entregan antecedentes, principalmente cualitativos de la presencia de estadios de desarrollo de copépodos parásitos, sobre determinadas larvas de peces costeros de la zona de la Bahía de Coliumo. De un muestreo efectuado en agosto y septiembre de 1981. se obtuvieron cinco formas larvales de peces parasitadas pertenecientes a Gobiesox marmoratus, Ophrogobrus jenynsi y otras tres no identificadas. Los parásitos se atribuyeron a representantes de Cahgidae y responden a estadios de copepoditos y de chalimus. Finalmente, se discuten algunos alcances relacionados con probables consecuencias ecológicas derivadas de la presencia de los parásitos registrados en las larvas de peces colectadas.

Renal disease is a common cause of morbidity and mortality in patients with plasma cell dyscrasias. The serum-free light chain assay is used in patients, mostly older, with unexplained acute kidney injury to screen for potential myeloma cast nephropathy. This study consists of a systematic review of diagnostic features in myeloma cast nephropathy. The morphological features of tubular casts in patients with multiple myeloma have not been systematically analyzed. This study focuses on the morphology of these casts, emphasizing ultrastructural features, in a series of 23 patients with light chain ("myeloma") cast nephropathy and compared them with casts in 10 patients with various diseases. The immunofluorescence data were correlated with morphological findings to provide diagnostic assessments and practice guidelines. The ultrastructural features identified as diagnostic of casts associated with myeloma included: amyloid and crystals in the casts, multiple well-defined fracture planes forming a complex jigsaw puzzle arrangement of cast contents, indicative of the fragility of the immunoglobulin light chains involved, and reactive tubular cells lining the tubules with the casts. These features were seen in 95.2% of MCN cases and none of the casts in other renal conditions. Myeloma casts exhibited light chain monoclonality in a significant percentage of the MCN cases and often no staining for IgA or IgM. In contrast, the majority of non-myeloma casts stained for both kappa and lambda light chains, lgA, and lgM, and showed ultrastructurally a rather uniform finely to coarsely granular electron density occasionally admixed with cellular debris.

Se determina tasas de crecimiento de larvas de anchoveta Engraulis ringens en la zona de Talcahuano (36°35'S), cerca del límite sur de distribución de la especie. Para estimar la edad se utilizó el número de anillos diarios en los otolitos. Los otolitos muestran un crecimiento alométrico en relación a la talla larval, y a la edad. Un modelo potencial y un modelo de Schnute proporcionaron el mejor ajuste para la relación longitud vs. edad, en el rango de tallas consideradas. Para fines prácticos preferimos considerar el primero debido a su mayor simplicidad. E. ringens muestra una baja tasa de crecimiento en la zona de estudio, debido probablemente a condiciones ambientales adversas.

Primary mandibular telangiectatic osteosarcomas are very rare lesions, with only nine cases reported. Histologically, these lesions show multiple cystic blood-filled cavities traversed by neoplastic bone in septa lined by high-grade malignant cells. Here, we report an 81-year-old woman who presented with a mandibular mass, which was surgically resected and analyzed by histologic examination and whole exome DNA sequencing. A diagnosis of telangiectatic osteosarcoma was given. Comparative sequencing data analysis of paired benign and tumor DNA revealed 1577 variants unique to the tumor DNA, which clustered into several gene families, including those regulating DNA repair and apoptosis. Comparison of benign and tumor DNA revealed many shared gene polymorphisms associated with an increased cancer risk. These included polymorphisms in the ATM, p53, BRCA1, and BRCA2 and many other genes. Interestingly, the patient's family history showed an unusually high cancer incidence, likely related to these cancer risk-associated polymorphisms. To our knowledge, this is the first-time sequencing applied to a mandibular telangiectatic osteosarcoma. Our findings may shed light on the molecular origins of these rare tumors and how they may relate to other tumors in related kindreds.

In this clinical case report, we present a rare subtype of amyloidosis, apolipoprotein CII (apo CII), which was diagnosed through a renal biopsy and subsequently confirmed by identifying the p.K41T mutation via germline DNA sequencing. Upon reviewing the literature, five patients exhibiting identical mutation were identified via renal biopsy, while an additional patient was diagnosed through biopsies of the fat pad and bone marrow. Notably, our patient is the youngest recorded case. We pioneered the application of immunofluorescence and immunogold electron microscopy techniques for apo CII evaluation. Our report provides a detailed description of this case, supplemented by an extensive review encompassing apo CII, documented instances of apo CII amyloidosis with renal or systemic involvement, and potential underlying mechanisms.

Primary pulmonary angiosarcomas are rare malignancies, with aggressive clinical behavior and poor prognosis. Here we present a case of a rare primary pulmonary epithelioid angiosarcoma in a 59-year-old woman who initially presented with right-sided chest pain and shortness of breath. Chest X-ray revealed right lower lobe atelectasis, while a chest computed tomography angiography (CTA) showed a large right hydrothorax with collapse of most of the right lung. A right lower lobe resection was performed and histologic and immunohistochemical analyses were consistent with a primary pulmonary epithelioid angiosarcoma. The patient was discharged, given supportive care, and died 12 days following her last operation.

The etiology of minimal change disease (MCD) remains a mystery as the only characteristic findings are the diffuse effacement of foot processes seen on electron microscopy (EM). Punctate IgG staining found floating outside glomerular capillary loops in MCD cases was recently identified as autoimmune antibodies against nephrin of podocytes. We hypothesized that the punctate IgG staining is located on budding ballooning clusters (BBC) of reactive foot processes in Bowman's space found on EM. We identified seven patients with MCD cases showing IgG staining that were subsequently evaluated for BBC on EM. We concurrently examined 12 negative controls, either unremarkable cases or tubulointerstitial diseases, by EM. Immunogold labeling was performed to confirm the presence of IgG and determine localization. In seven MCD cases, there were positive punctate IgG staining particles outside of the glomerular basement membranes (GBM) along with concurrent punctate staining for C3, kappa, and lambda. By EM, all seven (100%) MCD cases revealed BBC that was characterized by ballooning foot processes ranging from 1 to 6 mu m and was either budding or detached from the GBM in 3-7 clusters; no electron-dense materials were seen in BBC. BBC was also seen in only 1 of 12 (8%) negative controls. Immunogold labeling identified IgG particles within BBC of MCD by EM, but not in the negative control. Our data suggest that BBC are EM structures of reactive foot processes that are most likely correlated with punctate IgG staining seen in cases of MCD, supported by immunogold labeling for IgG.

Genetic screening and risk-reducing surgery have reduced the morbidity of epithelial ovarian cancer (EOC) and informed carcinogenesis. Here, we describe the crosstalk between the immune and epithelial compartments of BRCA1+ dysplastic fallopian tube (FT) lesions via spatially resolved transcriptomics. Immune and epithelial compartments of dysplastic FT were compared to normal FT segments to better evaluate the interaction between the immune milieu and the tubal epithelia during ovarian pathogenesis. Tissue blocks of a serous tubal intraepithelial carcinoma (STIC) containing BRCA1+ FT were procured. A 5 μm FFPE section was prepped and stained using the GeoMx Digital Spatial Profiler Protocol by Nanostring. Epithelial and immune compartments were labeled with morphology antibodies: PanCK and CD45, respectively. Regions of interest (ROI) +/− STIC were identified with pathology review and annotated. Photocleavable oligos attached to antibodies from the ROIs were exposed to UV light and released. The oligos were aspirated via microcapillary tube, stored in microplate wells, and quantified using next-generation sequencing Illumina workflows. Differential gene expression (DGE) of 4 STIC FT lesions was compared to normal FT using GeoMx Data Analysis software. Spatial deconvolution was performed to determine cell composition. Advaita iPathyway Guide was used to perform network analysis. DGE of STIC versus no STIC in the immune (CD45+) and epithelial (PanCK+) components identified 220 and 104 genes, respectively. Top DEGs in the immune/CD45+ dysplastic segments included upregulation of CLTC (LogFC 1.35; P = 3.2e-5) and decreased SND1 (LogFC -1.445; P = 9.5e-4). Network analysis of dysplastic CD45+ segments revealed hub genes involved in the immune response regulating cell-surface signaling and DNA damage/repair (DDR). The PanCK+ STIC compartment revealed significantly decreased expression of MAP3K6, a gene encoding ASK2, a tumor suppressor active in epithelial tumors (LogFC -0.707; P = 1.00e-4), and increased GPR171 expression, a G-protein coupled receptor recently found to suppress antitumor immunity (LogFC 0.652; P = 8.20e-4). Intriguingly, while spatial deconvolution of PanCK+ ROIs did not reveal significant differences in cell populations between STIC and normal, a trend toward a decrease in the leukocyte population in dysplastic lesions was noted. Our findings suggest there is a dynamic interplay between the immune system and dysplastic FT lesions years prior to the development of EOC. Immune evasion may be an early event in the course of carcinogenesis, and active STIC lesions may represent an escape from the equilibrium phase of tumor evasion through a mechanism previously undescribed in EOC, though further study to characterize STIC lesions is necessary. This work highlights the power of tissue profiling in a spatial context to inform pre-malignant EOC ecology.

Objectives To assess the prevalence of leukocyte cell-derived chemotactic 2 (LECT2), its organ involvement, and its clinical association in autopsies from an ethnically biased population. Methods The tissues from all autopsies of individuals diagnosed with amyloidosis were reassessed and typed for amyloid light chain (AL) amyloidosis, amyloid A (AA) amyloidosis, transthyretin amyloidosis (ATTR), and leukocyte chemotactic factor 2 amyloidosis (ALECT2) by immunohistochemistry. Organ involvement was described and correlated with its clinical associations. Results Of 782 autopsies, 27 (3.5%) had a confirmed diagnosis of amyloidosis. Of these, 14 (52%) corresponded to ALECT2, 5 (19%) to AL amyloidosis, 2 (7%) to ATTR amyloidosis, 1 (4%) to AA amyloidosis, and 5 (21%) as undetermined-type amyloidosis. The LECT2 amyloid deposits were found in the kidneys, liver, spleen, and adrenal glands in most individuals. Except for the kidneys, there were no clinical signs suggestive of amyloid deposition in most of the affected organs. LECT2 amyloidosis was not associated with the cause of death in any case. No cases had heart or brain involvement. Potential subclinical effects of amyloid deposition in organs such as adrenal glands and spleen require further study. Conclusions This autopsy study confirms the high prevalence of LECT2 amyloidosis in the Mexican population, with frequent amyloid deposition in the kidneys, liver, spleen, and adrenal glands.

The process of light-chain-associated amyloid (AL-Am) fibril formation in unique organelles (fibril-forming organelles) with lysosomal features has been documented in vitro in renal mesangial cells incubated with amyloidogenic light chains using electron microscopy and lysosomal gradient centrifugation to visualize intricate interactions between monoclonal light chains and endosomes/lysosomes. It is important to determine whether this process also occurs in vivo in the human renal mesangium. The present study analyzes 13 renal biopsies from patients with renal AL-amyloidosis and utilizes ultrastructural labeling techniques to define the nature and function of these organelles. Organelles were labeled for lysosomal-associated membrane protein (LAMP) and CD-68 (a macrophage marker). Furthermore, lambda was also localized inside these structures in transformed mesangial cells with a macrophage phenotype. These 11 cases from renal biopsies with a diagnosis of AL-amyloidosis (5 kappa and 8 lambda light-chain-associated) were examined ultrastructurally. All of the cases exhibited numerous fibrils forming organelles in approximately 40–50% of the remaining mesangial cells. All of the cases revealed mesangial cells engaged in active amyloidogenesis. Fibril-forming organelles are organelles with morphological/immunohistochemical and biochemical characteristics of lysosomes but with a unique, peculiar morphology. Five cases of other glomerular disorders used as controls were also carefully scrutinized for fibril-forming organelles and failed to show any. In the AL-amyloid renal cases, there was an intricate interaction between the fibril-forming organelles and lambda-/kappa-containing amyloid fibrils, supporting the notion that the monoclonal light chains participated in their formation.