Significance: Mismatch repair is the process that corrects replication errors. Mutations in the proteins MutSα and MutLα that initiate MMR are responsible for Lynch syndrome, the most common hereditary cancer. We present results showing surprising stoichiometries and conformations of human MutSα and MutLα mismatch repair initiation complexes. Moreover, these multimeric MutSα–MutLα complexes reconfigure the DNA in the vicinity of the mismatch. These complexes may not only mark the position of the mismatch but also could protect it from nucleosome reloading and potentially remodel adjacent nucleosomes. These results contrast with current models in the field, which envision mobile 1:1 MutSα–MutLα complexes that leave the mismatch. Our results provide a framework for thinking about MMR initiation.

Background.: Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate. Subnormothermic machine perfusion (SNMP) has the potential to combine the advantages of both approaches but has undergone limited investigation. Therefore, the present study sought to determine the suitability of SNMP for extended kidney preservation. Methods.: SNMP at 22–25 °C was performed on a portable device for 24 h with porcine kidneys. Graft assessment included measurement of mechanical parameters and biochemical analysis of the perfusate using point-of-care tests. To investigate the viability of kidneys preserved by SNMP, porcine kidney autotransplants were performed in a donation after circulatory death (DCD) model. SNMP was also compared with static cold storage (SCS). Finally, follow-up experiments were conducted in a subset of human kidneys to test the translational significance of findings in porcine kidneys. Results.: In the perfusion-only cohort, porcine kidneys all displayed successful perfusion for 24 h by SNMP, evidenced by stable mechanical parameters and biological markers of graft function. Furthermore, in the transplant cohort, DCD grafts with 30 min of warm ischemic injury demonstrated superior posttransplant graft function when preserved by SNMP in comparison with SCS. Finally, human kidneys that underwent 24-h perfusion exhibited stable functional and biological parameters consistent with observations in porcine organs. Conclusions.: These observations demonstrate the suitability and cross-species generalizability of subnormothermic machine perfusion to maintain stable kidney perfusion and provide foundational evidence for improved posttransplant graft function of DCD kidneys after SNMP compared with SCS.

Key Points: There is a modulatory effect between peritubular capillaries (PTCs) and areas of interstitial fibrosis and tubular atrophy (IFTA). The spatial architecture of non-IFTA PTCs on the cortex is significantly associated with glomerular disease progression. The shape of IFTA PTCs on the cortex is significantly associated with glomerular disease progression. Background: Interstitial fibrosis and tubular atrophy (IFTA) and density and shape of peritubular capillaries (PTCs) are independently prognostic of disease progression. The aim of this study was to identify novel digital biomarkers of disease progression and assess the clinical relevance of the interplay between a variety of PTC characteristics and their microenvironment in glomerular diseases. Methods: A total of 344 Nephrotic Syndrome Study Network/CureGN participants were included: 112 with minimal change disease, 134 with focal segmental glomerulosclerosis, 61 with membranous nephropathy, and 37 with IgA nephropathy. A periodic acid–Schiff–stained whole-slide image per patient was manually segmented for cortex, pre-, and mature IFTA. Interstitial fractional space (IFS) was computationally quantified. A deep learning model was applied to segment PTCs. Spatial and shape PTC pathomic features (230) were extracted from the cortex, IFTA, and non-IFTA subregions. Participants were divided into training and testing datasets (1:1). Univariate models incorporating IFTA subregions and IFS-PTC density were constructed. Least absolute shrinkage and selection operator regression models were used to identify the top PTC features associated with disease progression stratified by IFTA and non-IFTA subregions. Machine learning models were built using the top PTC features in IFTA and non-IFTA subregions to prognosticate disease progression. Results: PTC density in pre+mature IFTA and IFS, shape features in pre+mature IFTA, and spatial architecture features in the non-IFTA regions were associated with disease progression. The machine learning–generated risk scores showed a significant association with disease progression on the independent testing set. Conclusions: We uncovered previously under-recognized digital biomarkers of disease progression and the clinical relevance of the complex interplay between the status of the PTCs and interstitial microenvironment.

Atypical and malignant cutaneous tumors are understudied in the pediatric population, with limited data on long-term follow-up. This study examines pediatric (0–18 years) atypical melanocytic proliferations over a twenty-year period (January 2002–December2022) using the EPIC SlicerDicer at our institution. Over a twenty-year period, there were 55 cases of pediatric melanoma (53 patients). The median follow-up time was 8 years, 11 months. A proportion of 96% were treated with wide local excision (WLE), and 47% had a sentinel lymph node biopsy (SLNB) (35% positive rate). There were 101 atypical Spitz tumor cases (85% atypical Spitz tumors, 15% Spitz melanoma), with a median follow-up duration of 9 years. A proportion of 77% were treated with WLE (with one patient dying of metastatic disease). There were 10 cases of atypical melanocytic proliferations not otherwise specified, including 5 pigmented epithelioid melanocytomas (PEM), 4 deep-penetrating nevi, and 1 atypical cellular blue nevus. This study adds to the growing body of knowledge on pediatric atypical cutaneous melanocytic proliferations, aligning with many described characteristics such as disease location and overall survival rates, with distinct exceptions (higher melanoma positive SLNB rate, lower atypical Spitz tumor WLE rate, and a case of fatal metastatic atypical Spitz tumor).

Paraneoplastic cast nephropathy, a rare cause of acute kidney injury, is most commonly observed in cases of multiple myeloma and is characterized by the formation of intratubular casts composed of monoclonal light chains. Nonmonoclonal paraneoplastic cast nephropathy has also been reported in patients with pancreatic acinar cell carcinoma or prolactinoma. In this case report, we present a case of polyclonal cast nephropathy in a patient with metastatic acinar cell carcinoma. We aim to emphasize the significance of recognizing this uncommon complication in patients with solid tumors and to discuss the diagnostic challenges and potential pathophysiology of this unique condition.

Glomerular deposition of monoclonal IgM, frequently in the form of intracapillary pseudothrombi, can be seen in Waldenstr & ouml;m macroglobulinemia (WM) and type I cryoglobulinemia (CG). They are typically associated with plasma cell or B-lymphoid neoplasms, particularly lymphoplasmacytic lymphoma (LPL). While infection is a frequent trigger of mixed (type II and III) CG, its association with type I CG is uncommon. We report two cases in which striking lambda-chain-restricted IgM deposits and acute kidney injury (AKI) occurred in the setting of known or suspected systemic infections, with prompt resolution on treatment of the infection.