Monocyte Production of C1q Potentiates CD8+ T Cell Function Following Respiratory Viral Infection.

Respiratory viral infections remain a leading cause of morbidity and mortality. Using a murine model of human metapneumovirus (HMPV), we identified recruitment of a C1q-expressing inflammatory monocyte population concomitant with viral clearance by adaptive immune cells. Genetic ablation of C1q led to reduced CD8+ T cell function. Production of C1q by a myeloid lineage was necessary to enhance CD8+ T cell function. Activated and dividing CD8+ T cells expressed a C1q receptor, gC1qR. Perturbation of gC1qR signaling led to altered CD8+ T cell IFN-γ production, metabolic capacity, and cell proliferation. Autopsy specimens from fatal respiratory viral infections in children demonstrated diffuse production of C1q by an interstitial population. Humans with severe COVID-19 infection also demonstrated upregulation of gC1qR on activated and rapidly dividing CD8+ T cells. Collectively, these studies implicate C1q production from monocytes as a critical regulator of CD8+ T cell function following respiratory viral infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Schwannian and Perineuriomatous Differentiation in a Series of Giant Congenital Melanocytic Nevi.

ABSTRACT: Close relationship between melanocytes and neural cells is accepted to reflect their common derivation from the neural crest and tumors combining both elements. We present a series of 10 patients with giant congenital melanocytic nevi (CMN) in which a secondary proliferation (11 lesions) with schwannian and/or perineuriomatous differentiation developed in the course of the disease. The age of the patients (4 male and 6 female) at the time of surgery and histological assessment varied from 3 months to 57 years. Histopathologically, the following subgroups were delineated: (1) nodular/tumoriform "neurotization" in CMN, (2) diffuse neurofibroma-like proliferation within CMN, (3) plexiform neurofibroma-like proliferation within CMN, and (4) diffuse perineuriomatous (hybrid schwannomatous-perineuriomatous) differentiation in CMN. We review the pertinent literature, including the role of recently identified Schwann cell precursors which are believed to represent the nerve-associated state of neural crest-like cells that persists into later developmental stages.

Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes.

BACKGROUND & AIMS: Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA. METHODS: We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models. RESULTS: A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA. CONCLUSIONS: BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes. IMPACT AND IMPLICATIONS: Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.

Pediatric BCOR-Altered Tumors From Soft Tissue/Kidney Display Specific DNA Methylation Profiles.

In the pediatric population, BCL6-correpresor gene (BCOR)-upregulated tumors include primitive myxoid mesenchymal tumors/undifferentiated sarcomas (PMMTI/UND), clear cell sarcomas of the kidney (CCSK), and high-grade neuroepithelial tumors (HG-NET). We investigated DNA methylation (DNAm) and copy number variation (CNV) profiling in these tumors (N = 34) using an Illumina EPIC BeadChip to better define the potential use of these tools to confirm diagnosis and predict outcomes. Twenty-seven tumors from 25 patients (age range, 0-10 years), showed molecular confirmation of genetic abnormalities as follows: BCOR internal tandem duplication in 14 PMMTI/UND, 8 CCSK, and 3 HG-NET and YWHAE fusions in 2 PMMTI/UND. The remaining 7 cases lacking informative molecular data were analyzed by immunophenotyping and were included in the study as a training cohort, clearly separated from the main study group. These were 4 PMMTI, 1 HG-NET, and 1 CCSK in which poor RNA preservation precluded the confirmation of BCOR rearrangements and 1 CCSK in which no rearrangements were found. DNAm data were compared with those of brain tumor and/or sarcoma classifier. Differentially methylated regions (DMRs) were analyzed in the 3 groups. Twenty-two cases of the 24 molecularly confirmed PMMTI/UND and CCSK and 3 of 6 of those with only immunophenotyping were classified within the methylation class "BCOR-altered sarcoma family" with optimal calibrated scores. PMMTI/UND and CCSK showed similar methylation profiles, whereas thousands of DMRs and significantly enriched pathways were evident between soft tissue/kidney tumors and HG-NET. The CNV analysis showed an overall flat profile in 19 of the 31 evaluable tumors (8/10 CCSK; 9/18 PMMTI/UND; 2/4 HG-NET). The most frequent CNVs were 1q gain and 9p and 10q loss. Follow-up time data were available for 20 patients: ≥2 CNV significantly correlated with a worse overall survival rate. In conclusion, soft tissue and kidney BCOR sarcomas matched with BCOR-altered sarcoma methylation class, whereas those from the brain matched with the central nervous system tumor classifier HG-NET BCOR, supporting the notion that DNAm profiling is an informative diagnostic tool. CNV alterations were associated with a more aggressive clinical behavior.

Liver transplantation for alpha 1 antitrypsin deficiency (A1ATD) using a heterozygous donor: Outcomes and review of the literature.

INTRODUCTION: Alpha 1 antitrypsin deficiency (A1ATD) accounts for 21% of all pediatric liver transplants due to metabolic disease in the western world. Donor heterozygosity has been evaluated in adults but not to a recipient with A1ATD. METHODS: The data of patient were retrospectively analyzed and a literature review performed. RESULTS: We present a unique case of living related donation from a A1ATD heterozygote female to a child for decompensated cirrhosis due to A1ATD. In the immediate postoperative period, the child had low-alpha 1 antitrypsin levels, but these normalized by 3 months posttransplant. He is currently 19 months post-transplant with no evidence of recurrent disease. CONCLUSION: Our case provides initial evidence that A1ATD heterozygote donors may be safely used for pediatric patients with A1ATD, thus expanding the donor pool.

Successful Treatment of Patient With Ewing Sarcoma in the Setting of Inherited Cholestatic Liver Disease.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited, progressive cholestatic liver disease. Here, we present an approach to the treatment of Ewing sarcoma in a patient with PFIC1. The diagnosis of PFIC1 presents a unique challenge in the treatment of Ewing sarcoma, as the standard-of-care vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide chemotherapy backbone for Ewing sarcoma therapy treatment relies heavily on intact hepatic metabolism. In addition, we report prolonged lymphopenia and severe infectious complications in this patient, both of which may be attributed to more severe immunosuppression in setting of poor hepatic metabolism of chemotherapeutic agents.

Potter Deformation Sequence Caused by 17q12 Deletion: A Lethal Constellation.

17q12 deletion syndrome causes developmental abnormalities of the kidneys, pancreas, genital tract, and neurodevelopment, and it has a wide range of phenotypes ranging from fetal demise to normal adulthood with minimal renal impairment. Here we describe a rare case of 17q12 deletion diagnosed prenatally, complicated by anhydramnios and Potter sequence. The baby was born but necessitated life-saving interventions due to pulmonary and renal insufficiency and ultimately succumbed to multi-organ failure. We present full autopsy results describing findings linked to 17q12 deletion, including severe bilateral multicystic renal dysplasia, pancreatic hypoplasia, and cysts adjacent to the Fallopian tubes. We also describe pulmonary hypoplasia and Potter facies as consequences of anhydramnios. We correlate these findings to our current understanding of molecular signals altered by 17q12 deletion, notably affecting HNF1B and LHX1 genes, which are known to mediate renal and genitourinary tract development.

Alpelisib decreases nevocytes of congenital melanocytic nevi.

BACKGROUND: Multiple, large or giant congenital melanocytic nevi (CMN) are uncommon and affected patients can show progressive growth and thickening, associate neurocutaneous melanocytosis or develop melanoma. Current treatment modalities are mostly complex surgeries that frequently do not solve the disease and its risks completely. Thus, investigation on new treatment options for CMN and its complications must continue. MAPK pathway inhibitors are being investigated, also targeting PI3K-AKT. Omipalisib (PI3K inhibitor, with no indications approved yet) has been studied for CMN in vitro and in mice with promising results. However, alpelisib, a PI3K inhibitor approved with an adequate safety profile for patients with severe manifestations of PROS (PIK3CA-Related Overgrowth Spectrum), had not yet been tested for CMN. OBJECTIVE: To evaluate the effect of alpelisib in nevocytes of congenital melanocytic nevi. METHODS: Nevomelanocytic tissue samples of 10 patients were collected prospectively and, following a previously reported preclinical ex vivo model, explants were placed in organotypic culture for 5 days, with or without alpelisib. Consecutively, tissue sections were stained and using scanned images with Qupath and ImageJ softwares, representative regions from the dermis were analysed (using Wilcoxon test and Spearman's correlation). RESULTS: When comparing alpelisib-treated explants with respect to control explants, we found a decrease in cell density (p = 0.0273), in density of SOX10+ -cells (p = 0.0391) and also in the % of S-100+ area (p = 0.0078), in alpelisib samples. The three markers showed a positive correlation (p < 0.05). CONCLUSIONS: This study provides first-time evidence that alpelisib induces nevocyte reduction in CMN from patient-derived explants, probably inducted by autophagy. Alpelisib is an approved drug with an adequate safety profile used in another mosaicism affecting PI3K (PROS). Further studies are needed to evaluate its efficacy in treating CMN and potentially, their complications, either with local or systemic administration, alone or in combination.

Cutaneous Ewing Sarcoma Presenting as a Second Primary Malignancy in a Child.

Ewing sarcoma is an EWS-ETS family member-driven malignancy that most commonly arises from bone. Cutaneous Ewing sarcoma is a rare variant which harbors an EWS-ETS family fusion but demonstrates an immunohistochemical staining pattern distinct from classic Ewing tumors. EWSR1 fluorescence in situ hybridization testing interpretation can be challenging in the setting of cutaneous Ewing sarcoma, making an integrated histologic and sequencing approach key for an accurate diagnosis. Here, we report a pediatric patient with a history of neuroblastoma treated with surgery only that developed a cutaneous nodule and was diagnosed with cutaneous Ewing sarcoma as a second primary cancer.

NEMO-NDAS: A Panniculitis in the Young Representing an Autoinflammatory Disorder in Disguise.

ABSTRACT: A 15-month-old full-term boy of African descent with an asymptomatic sickle cell trait presented with episodes of transient erythematous subcutaneous nodules involving the entire body except the face, since 2 weeks of age. The skin lesions evolved to areas of lipoatrophy and hyperpigmentation. An initial skin biopsy, studied at a different department at 2 months, was initially misinterpreted as subcutaneous fat necrosis of the newborn, despite the lack of the typical radiated crystals and needle-shaped clefts characterizing that entity. At 4 months of age, he developed systemic inflammatory manifestations, including fever, a new rash, significant periorbital edema, and failure to thrive. An extensive workup showed leukocytosis, hypercalcemia, elevated inflammatory markers, hypertriglyceridemia, and transaminitis. A new skin biopsy of the eyelid was diagnosed as neutrophilic lobular panniculitis with necrotic adipocytes. An initial whole-exome sequencing did not identify any causative mutations, but a WES reanalysis focused on autoinflammatory disorders was requested based on additional clinicopathologic data and revealed a mosaic intronic mutation in IKBKG c. 671+3 G > C. This mutation encodes an mRNA missing exon 5 resulting in NF-kB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NDAS). NEMO-NDAS is one of the systemic autoinflammatory diseases that may appear as an unexplained panniculitis in young children, who should be monitored for immunodeficiency and/or autoinflammatory diseases. The differential diagnosis of autoinflammatory disorders should be considered in such cases incorporating the use of the whole-genome/exome sequencing in the investigation. The inhibitor of kappa-B kinase regulatory subunit gamma (IKBKG) is located on chromosome Xq28 and encodes the NEMO, a critical molecule upstream of NF-kB activation.

Morphologic Spectrum of Rhabdomyomatous Mesenchymal Hamartomas (Striated Muscle Hamartomas) in Pediatric Dermatopathology.

BACKGROUND: Rhabdomyomatous mesenchymal hamartomas (RMHs), also termed striated muscle hamartomas, are rare benign tumors of skin and subcutis, which mostly occur at birth with a predilection for the head and neck. Simple surgical excision is the treatment modality of choice with excellent prognosis. OBJECTIVE: To review the spectrum of the different clinical and pathologic features of RMHs in pediatric patients and recognize their characteristics to avoid confusion with other lesions in their list of differential diagnosis. METHODS: Six cases of RMH diagnosed at our institution from 2009 to 2021 were retrieved from our files and reviewed retrospectively after anonymization by an honest broker. This review is IRB-approved by the University of Pittsburgh School of Medicine, study STUDY19080192. RESULTS: The patients' age ranged from 6 days to 8 years, with a female predominance (2:1). In all cases, the lesion was present at birth. All lesions, except for 2, occurred in the head and neck regions. One patient had multiple additional small nodules in the face, whereas all others presented with solitary RMHs. The size of the lesions varied, and their composition included bundles of skeletal muscle (the landmark finding) associated with variable amounts of adipose, fibrous, vascular, nerve, and adnexal structures. CONCLUSIONS: RMH is a benign hamartomatous lesion with a variable phenotypic spectrum. RMHs predominate in the head and neck. Familiarity with these lesions, including their presentation in less frequent anatomical sites, is important to avoid diagnostic misinterpretations and potential overtreatment. This study represents one of the largest series of RMHs in the literature, including an unusual case in a perianal location.

Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2.

Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome resulting from defective cytotoxicity. A previously healthy 3-month-old female presented with fever, irritability, abdominal distention, and tachypnea. She ultimately met all eight HLH-2004 diagnostic criteria, accompanied by elevated CXCL9. Initial empiric anti-inflammatory treatment included anakinra and IVIg, which stabilized ferritin and cytopenias. She had molecular and genetic confirmation of perforin deficiency and was started on dexamethasone and etoposide per HLH-94. She clinically improved, though CXCL9 and sIL-2Ra remained elevated. She was readmitted at week 8 for relapsed HLH without clear trigger and HLH-94 induction therapy was reinitiated. Her systemic HLH symptoms failed to respond and she soon developed symptomatic CNS HLH. She was incidentally found to have multifocal lung and kidney nodules, which were sterile and consisted largely of histiocytes and activated, oligoclonal CD8 T cells. The patient had a laboratory response to salvage therapy with alemtuzumab and emapalumab, but progressive neurologic decline led to withdrawal of care. This report highlights HLH foci manifest as pulmonary/renal nodules, demonstrates the utility of monitoring an array of HLH biomarkers, and suggests possible benefit of earlier salvage therapy.

Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience.

BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. METHODS: We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. RESULTS: Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. CONCLUSION: We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.

A study of dermal melanophages in childhood nevi. Reassessing so-called "pigment incontinence".

In inflammatory dermatoses, dermal melanophages (MLP) are ascribed to "pigment incontinence," with melanin "dropping down" from the epidermis. Although this is analogous to the "dropping down" of melanocytic nevus cells (Abtropfung), MLP in ordinary nevi have not been systematically studied-so "pigment incontinence" may not apply to MLP in nevi. A total of 31 childhood nevi identified by pediatricians and family practitioners were evaluated for the distribution of MLP. We tested the hypothesis that a dermal origin of the melanin in MLP is more likely than dropping down from the epidermis. In our cohort, 90.3% (28/31) of childhood nevi had dermal MLP, a significantly higher frequency, compared to 31/60 ordinary adult nevi (P < 0.0001). Superficial dermis was the most common location (P < 0.001). However, only six specimens had MLP restricted to the superficial dermis, significantly less than predicted by the theory that melanin drops down from the epidermis (P < 0.00001). We also evaluated perivascular MLP, since nerves run together with vessels in neurovascular bundles (NVB), and it has been showed that precursors of melanocytes migrate from the neural crest to the skin as nerve sheath stem cells. Superficial NVB MLP correlated with deep NVB bundle MLP (P < 0.05), suggesting that NVB MLP represent "tombstones" for superficial and deep dermal nevus cells. Deep dermal, deep NVB, and deep periadnexal MLP may be valid biological criteria for diagnosis of congenital type (prenatal) nevi. Viewing prenatal nevi in children as a neurocristopathy fits a major principle of pediatric pathology: childhood diseases should be studied and understood based on what happens during tissue development.

Pediatric Soft Tissue Tumors With BCOR ITD Express EGFR but Not OLIG2.

INTRODUCTION: Somatic internal tandem duplication of 3' of BCOR (BCOR ITD) has been found in clear cell sarcomas of the kidney (CCSK), soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and a subgroup of central nervous system high-grade neuroepithelial tumors (CNS-HGNET). BCOR ITD+ tumors share morphologic features. Expression of OLIG2 and epidermal growth factor receptor (EGFR) has been reported in CNS-HGNET with BCOR ITD. Here, we characterize OLIG2 and EGFR expression in URCS/PMMTI with BCOR ITD. METHODS: Paraffin blocks of 9 polymerase chain reaction-confirmed soft tissue BCOR ITD+ tumors (URCS/PMMTI) were immunophenotyped for OLIG2 and EGFR expression and scored semiquantitatively by percentage of positive cells and intensity of staining as negative, 1+, 2+, and 3+. Fluorescence in situ hybridization (FISH) for EGFR amplification was performed (amplification EGFR/CEP7 ratio ≥2.0). RESULTS: All 9 tumors showed membrane/cytoplasmic expression of EGFR, strong and diffuse (3+) in 8 cases; weak (+2) in 1. FISH detected no EGFR amplification. OLIG2 was negative in all. CONCLUSIONS: EGFR is overexpressed in pediatric URCS/PMMTI with BCOR ITD and may be related to transcriptional upregulation of EGFR by BCOR ITD. OLIG2 negative staining differentiates URCS/PMMTI from CNS-HGNET. This finding may further support the possibility that these tumors have a different stem cell of origin.

Diffuse myocardial fibrosis among healthy pediatric heart transplant recipients: Correlation of histology, cardiovascular magnetic resonance, and clinical phenotype.

Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation.

Morphologic and Ancillary Studies of Pediatric Acinic Cell Carcinoma: A Single Institute Experience.

BACKGROUND: Acinic cell carcinoma (AciCC) is the second most common pediatric malignant salivary gland tumor. However, there are limited pathology publications about this tumor in the pediatric population. METHODS: We describe four pediatric AciCC cases diagnosed between 2000 and 2021 in our institute. Reticulin histochemistry plus immunohistochemistry for NR4A3 and DOG1 were performed on all cases. RESULTS: Histologically, all four cases featured a tumor-associated lymphoid proliferation and collagenous stroma, in which two formed central scars. The tumors were predominantly solid, with a lobular pattern and variably sized dilated spaces, including one case with focal microcysts. High-grade transformation was not observed in any of our cases. Reticulin stain and immunohistochemistry for NR4A3 showed distinct features between AciCC and non-neoplastic salivary gland parenchyma. DOG1 immunohistochemistry confirmed the acinar origin of AciCC. CONCLUSIONS: Our study reveals that pediatric AciCCs often present with tumor-associated lymphoid proliferation (TALP) and sclerosis. Special stains such as reticulin histochemistry and NR4A3 immunohistochemistry are helpful to separate tumor from adjacent benign parenchyma. The ancillary study is helpful for the diagnosis of small specimens. Our study is limited by its low case number, but we hope that our results will promote more studies on this rare salivary gland tumor in the pediatric population.

Monocyte production of C1q potentiates CD8 + T cell effector function following respiratory viral infection.

Respiratory viral infections remain a leading cause of morbidity and mortality. Using a murine model of human metapneumovirus (HMPV), we identified recruitment of a C1q-producing inflammatory monocyte population concomitant with viral clearance by adaptive immune cells. Genetic ablation of C1q led to reduced CD8 + T cell function. Production of C1q by a myeloid lineage was sufficient to enhance CD8 + T cell function. Activated and dividing CD8 + T cells expressed a putative C1q receptor, gC1qR. Perturbation of gC1qR signaling led to altered CD8 + T cell IFN-γ production and metabolic capacity. Autopsy specimens from fatal respiratory viral infections in children demonstrated diffuse production of C1q by an interstitial population. Humans with severe COVID-19 infection also demonstrated upregulation of gC1qR on activated and rapidly dividing CD8 + T cells. Collectively, these studies implicate C1q production from monocytes as a critical regulator of CD8 + T cell function following respiratory viral infection.

Mesenchymal chondrosarcoma of the chest wall in an adolescent patient: A case report and brief review of the literature.

BACKGROUND: Mesenchymal chondrosarcoma is a rare and aggressive bone tumor with few reports of primary tumor in the chest wall. CASE: We report a case of a 17-year-old male presenting with back pain and a posterior mediastinal mass. Imaging demonstrated what was thought to be a benign chondral tumor. The patient underwent resection which confirmed extraskeletal mesenchymal chondrosarcoma. The patient declined proposed adjuvant chemotherapy and underwent multiple resections for rapid local reoccurrence. He ultimately elected for hospice care. CONCLUSION: The case highlights the importance of close disease monitoring and exploration of treatment options, given lack of established guidelines and consistent tumor features.