Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer.

Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Here we integrated topological maps for colon tumors and normal colons with epigenetic, transcriptional, and imaging data to characterize alterations to chromatin loops, topologically associated domains, and large-scale compartments. We found that spatial partitioning of the open and closed genome compartments is profoundly compromised in tumors. This reorganization is accompanied by compartment-specific hypomethylation and chromatin changes. Additionally, we identify a compartment at the interface between the canonical A and B compartments that is reorganized in tumors. Remarkably, similar shifts were evident in non-malignant cells that have accumulated excess divisions. Our analyses suggest that these topological changes repress stemness and invasion programs while inducing anti-tumor immunity genes and may therefore restrain malignant progression. Our findings call into question the conventional view that tumor-associated epigenomic alterations are primarily oncogenic.

A positively selected FBN1 missense variant reduces height in Peruvian individuals.

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

De novo membranous nephropathy in a pig-to-baboon kidney xenograft: A new xenograft glomerulopathy.

De novo membranous nephropathy (dnMN) is an uncommon immune complex-mediated late complication of human kidney allografts that causes proteinuria. We report here the first case of dnMN in a pig-to-baboon kidney xenograft. The donor was a double knockout (GGTA1 and ß4GalNT1) genetically engineered pig with a knockout of the growth hormone receptor and addition of 6 human transgenes (hCD46, hCD55, hTBM, hEPCR, hHO1, and hCD47). The recipient developed proteinuria at 42 days posttransplant, which progressively rose to the nephrotic-range at 106 days, associated with an increase in serum antidonor IgG. Kidney biopsies showed antibody-mediated rejection (AMR) with C4d and thrombotic microangiopathy that eventually led to graft failure at 120 days. In addition to AMR, the xenograft had diffuse, global granular deposition of C4d and IgG along the glomerular basement membrane on days 111 and 120. Electron microscopy showed extensive amorphous subepithelial electron-dense deposits with intervening spikes along the glomerular basement membrane. These findings, in analogy to human renal allografts, are interpreted as dnMN in the xenograft superimposed on AMR. The target was not identified but is hypothesized to be a pig xenoantigen expressed on podocytes. Whether dnMN will be a significant problem in other longer-term xenokidneys remains to be determined.

Author Correction: High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.

In Fig. 4e of this Article, the labels for 'Control' and 'HFD' were reversed ('Control' should have been labelled blue rather than purple, and 'HFD' should have been labelled purple rather than blue). Similarly, in Fig. 4f of this Article, the labels for 'V' and 'GW' were reversed ('V' should have been labelled blue rather than purple, and 'GW' should have been labelled purple instead of blue). The original figure has been corrected online.

Prognostic Significance of Percentage and Size of Dedifferentiation in Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma is rare, aggressive, and microscopically bimorphic. How pathologic features such as the amounts of dedifferentiation affect prognosis remains unclear. We evaluated the percentages and sizes of dedifferentiation in a consecutive institutional series of dedifferentiated chondrosarcomas from 1999 to 2021. The statistical analysis included cox proportional hazard models and log-rank tests. Of the 67 patients (26 women, 41 men; age, 39 to >89 [median 61] years; 2 with Ollier disease), 58 presented de novo; 9 were identified with conventional chondrosarcomas 0.6-13.2 years (median, 5.5 years) prior. Pathologic fracture and distant metastases were noted in 27 and 7 patients at presentation. The tumors involved the femur (n = 27), pelvis (n = 22), humerus (n = 7), tibia (n = 4), scapula/ribs (n = 4), spine (n = 2), and clivus (n = 1). In the 56 resections, the tumors ranged in size from 3.5 to 46.0 cm (median, 11.5 cm) and contained 1%-99.5% (median, 70%) dedifferentiated components that ranged in size from 0.6 to 24.0 cm (median, 7.3 cm). No correlation was noted between total size and percentage of dedifferentiation. The dedifferentiated components were typically fibrosarcomatous or osteosarcomatous, whereas the associated cartilaginous components were predominantly grade 1-2, rarely enchondromas or grade 3. The entire cohort's median overall survival and progression-free survival were 11.8 and 5.4 months, respectively. In the resected cohort, although the total size was not prognostic, the percentage of dedifferentiation ≥20% and size of dedifferentiation >3.0 cm each predicted worse overall survival (9.9 vs 72.5 months; HR, 3.76; 95% CI, 1.27-11.14; P = .02; 8.7 vs 58.9 months; HR, 3.03; 95% CI, 1.21-7.57; P = .02, respectively) and progression-free survival (5.3 vs 62.1 months; HR, 3.05; 95% CI, 1.13-8.28; P = .03; 5.3 vs 56.6 months; HR, 2.50; 95% CI, 1.06-5.88; P = .04, respectively). In conclusion, both the percentages and sizes of dedifferentiation were better prognostic predictors than total tumor sizes in dedifferentiated chondrosarcomas, highlighting the utility of their pathologic evaluations.

A missense variant in SLC39A8 confers risk for Crohn's disease by disrupting manganese homeostasis and intestinal barrier integrity.

Common genetic variants interact with environmental factors to impact risk of heritable diseases. A notable example of this is a single-nucleotide variant in the Solute Carrier Family 39 Member 8 (SLC39A8) gene encoding the missense variant A391T, which is associated with a variety of traits ranging from Parkinson's disease and neuropsychiatric disease to cardiovascular and metabolic diseases and Crohn's disease. The remarkable extent of pleiotropy exhibited by SLC39A8 A391T raises key questions regarding how a single coding variant can contribute to this diversity of clinical outcomes and what is the mechanistic basis for this pleiotropy. Here, we generate a murine model for the Slc39a8 A391T allele and demonstrate that these mice exhibit Mn deficiency in the colon associated with impaired intestinal barrier function and epithelial glycocalyx disruption. Consequently, Slc39a8 A391T mice exhibit increased sensitivity to epithelial injury and pathological inflammation in the colon. Taken together, our results link a genetic variant with a dietary trace element to shed light on a tissue-specific mechanism of disease risk based on impaired intestinal barrier integrity.

Hepatic histologic findings in a case of MEGDHEL syndrome due to SERAC1 deficiency.

MEGD(H)EL syndrome is a rare autosomal recessive disorder caused by mutations in SERAC1, a protein necessary for phosphatidylglycerol remodeling. It is characterized by 3-methylglutaconic aciduria, deafness-dystonia, (hepatopathy), encephalopathy, and Leigh-like syndrome, but has a wide spectrum of severity. Here, we present a case of a child with MEGD(H)EL syndrome with infantile hepatopathy, neurodevelopmental delays, characteristic biochemical abnormalities, and biallelic novel SERAC1 mutations: (1) deletion of (at least) exons 2-4, pathogenic; and (2) c.1601A>T (p.H534L), likely pathogenic. Her initial clinical presentation was notable for persistently elevated transaminases, speech delay, delayed motor milestones, and sensorineural hearing loss. However, her verbal and motor development has progressively improved and now, at 4 years of age, she has only speech and mild gross motor delays as compared to her unaffected peers and is exceeding clinical expectations. The histologic features of a liver biopsy are described, which has not previously been published in detail for this syndrome. Hepatocytes showed granular cytoplasm and fine intracytoplasmic lipid droplets. The ultrastructural findings included abnormal circular mitochondrial cristae. These findings are consistent with a mitochondrial disorder.

High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.

Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-δ recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.

Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma.

BACKGROUND: Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. METHODS: Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes. RESULTS: Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. CONCLUSION: A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors. IMPLICATIONS FOR PRACTICE: This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.

Thoracic nuclear protein in testis (NUT) carcinoma: expanded pathological spectrum with expression of thyroid transcription factor-1 and neuroendocrine markers.

AIMS: Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor-1 (TTF-1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum. METHODS AND RESULTS: We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA-based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31-80 years; four never-smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3-12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF-1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT-positive cases were found by immunohistochemical screening. CONCLUSIONS: Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF-1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive-appearing tumours, regardless of their immunophenotypic features.

Amyloid Arthropathy: A Review.

Amyloid arthropathy is a joint disease associated with systemic amyloidosis. Herein, we present a model case and review the clinicopathologic features and pathophysiology of this disorder. Amyloid arthropathy results from elevation of serum amyloidogenic proteins and their deposition as aggregates in synovial fluid and articular tissues. The most common proteins are beta-2-microglobulin in the context of long-term hemodialysis therapy and immunoglobulin light chains associated with plasma cell proliferations. We provide a comprehensive update on the pathogenesis, clinical manifestations, and pathologic features of amyloid arthropathy. We provide detailed insights on amyloid protein deposition and aggregation in joints and proper details for diagnosis.

Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.

Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions.

Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20-66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1-KMT2A-YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.

Complement 7 Is Up-Regulated in Human Early Diabetic Kidney Disease.

There is a temporal window from the time diabetes is diagnosed to the appearance of overt kidney disease during which time the disease progresses quietly without detection. Currently, there is no way to detect early diabetic nephropathy (EDN). Herein, we performed an unbiased assessment of gene-expression analysis of postmortem human kidneys to identify candidate genes that may contribute to EDN. We then studied one of the most promising differentially expressed genes in both kidney tissue and blood samples. Differential transcriptome analysis of EDN kidneys and matched nondiabetic controls showed alterations in five canonical pathways, and among them the complement pathway was the most significantly altered. One specific complement pathway gene, complement 7 (C7), was significantly elevated in EDN kidney. Real-time PCR confirmed more than a twofold increase of C7 expression in EDN kidneys compared with controls. Changes in C7 gene product level were confirmed by immunohistochemistry. C7 protein levels were elevated in proximal tubules of EDN kidneys. Serum C7 protein levels were also measured in EDN and control donors. C7 levels were significantly higher in EDN serum than control serum. This latter finding was independently confirmed in a second set of blood samples from a previously collected data set. Together, our data suggest that C7 is associated with EDN, and can be used as a molecular target for detection and/or treatment of EDN.

A Conserved Distal Lung Regenerative Pathway in Acute Lung Injury.

Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsy specimens showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages. This novel constellation was termed diffuse alveolar injury with delayed epithelization. In addition, mirroring data from murine models of lung injury/regeneration, peribronchiolar basaloid pods (previously described as squamous metaplasia) and ciliated bronchiolarization were identified in these patients and in 39% of 57 historical cases with diffuse alveolar damage. These findings demonstrate a common and clinically relevant human disease correlate for murine models of severe acute lung injury. Evidence suggests that peribronchiolar basaloid pods and bronchiolarization are related spatially and temporally and likely represent overlapping sequential stages of the response to severe distal airway injury.

Multiple calcifying fibrous pseudotumors of the pleura: ultrastructural analysis provides insight on mechanism of dissemination.

Calcifying fibrous pseudotumor (CFP) is a rare, benign soft tissue tumor that may uncommonly arise in the pleura. These tumors can show multifocal dissemination across the pleural surface, but the mechanism underlying this dissemination is unclear. Review of previously reported cases of pleural CFP demonstrates a strong predilection for basal and diaphragmatic pleural surfaces, and a significantly higher rate of multifocality compared with other locations. We present a 59-year-old male with multiple CFP of the pleura. Reactive-appearing adhesions spanning the pleural surfaces were present, and by electron microscopy, were involved by tumor. We suggest this is the likely mode of dissemination across the pleural surfaces.

Myoepithelioma of bone: ultrastructural, immunohistochemical and molecular study of three cases.

Primary intraosseous myoepithelial tumors are rare neoplasms with only a handful of cases described in the medical literature. To date, intraosseous variant of benign myoepithelioma, due to its rarity, has not been studied ultrastructurally, and only one case of a malignant intraosseous myoepithelioma has been described. Three cases were retrieved from the files at the Massachusetts General Hospital (MGH). A diagnosis of benign myoepithelioma was made in case 1 and malignant epithelioma in cases 2 and 3. Ultrastructurally, intermediate filaments (without dense bodies) were found in each case with an abundance in case 1 and lesser amounts in cases 2 and 3. Surprisingly, cell junctions were not identified in case 1. However, they were found occasionally as intermediate junctions in case 2 and were easily identified as desmosome like junctions in case 3. The nucleus was irregular in the neoplastic cells of benign myoepithelioma which contrasted with cases 2 and 3 where the nuclei were oval yet had visible nucleoli. Herein, we add three new cases, including two new cases of malignant myoepithelioma. We also provide the first ultrastructural description of benign myoepithelioma of bone.

DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome.

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.

mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake.

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells­an ectoenzyme that produces the paracrine factor cyclic ADP ribose­mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.

Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model.

Hearing loss is the main limitation of radiation therapy for vestibular schwannoma (VS), and identifying treatment options that minimize hearing loss are urgently needed. Treatment with bevacizumab is associated with tumor control and hearing improvement in neurofibromatosis type 2 (NF2) patients; however, its effect is not durable and its mechanism of action on nerve function is unknown. We modeled the effect anti-VEGF therapy on neurological function in the sciatic nerve model and found that it improves neurological function by alleviating tumor edema, which may further improve results by decreasing muscle atrophy and increasing nerve regeneration. Using a cranial window model, we showed that anti-VEGF treatment may achieve these effects via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation. It is known that oxygen is a potent radiosensitizer; therefore, we further demonstrated that combining anti-VEGF with radiation therapy can achieve a better tumor control and help lower the radiation dose and, thus, minimize radiation-related neurological toxicity. Our results provide compelling rationale for testing combined therapy in human VS.