MYC sensitises cells to apoptosis by driving energetic demand.

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Gastric Electrical Stimulation Has an Effect on Gastric Interstitial cells of Cajal (ICC) That is Associated With Mast Cells.

Introduction Gastric electrical stimulation (GES) is an emerging therapy for gastric motility disorders, showing improvement of gastroparesis related symptoms in previous studies. Interstitial cells of Cajal (ICC) and mast cells have been shown to have a relevant role in gastroparesis pathogenesis. However, the exact effects of GES in those cells is relatively unknown. Methods Full thickness biopsies (FTBx) of 20 patients with refractory gastroparesis were obtained at the time of GES placement and repeated when the device was exchanged (mean of 22.5 months between biopsies). A patient-reported outcomes survey was obtained during each office visit during this period. All biopsies were stained with cluster of differentiation 117 (CD117), S100, and mast cell tryptase antibodies and were analyzed. Results Half of the patients had a significant increase of ICC during the repeated biopsy compared with baseline (p=0.01) and the other half had significant decrease in ICC levels (p=0.006) but there was no noticeable difference in mast cells counts at baseline between groups. Mast cells analysis was performed in two different groups depending on ICC change from the baseline biopsy (CD117 increase vs CD117 decrease). There was only a significant increase of mast cells count within the CD117 worsened ICC group (p=0.007). Conclusion No significant increase in the number of mast cells count seen in patients who received a GES may indicate an improvement in overall inflammation in patients with refractory gastroparesis after GES placement.

Giant pigmented apocrine hidrocystoma of the scalp.

Hidrocystomas are benign cysts of sweat duct epithelium that can present as single or multiple lesions, with or without pigmentation. The size is typically 1-3mm in diameter. Although hidrocystomas commonly occur in most parts of the head and neck region, occurrence on the scalp is rare. Herein, we present a 29-year-old woman with a giant pigmented apocrine hidrocystoma of the scalp, which, to our knowledge, represents the largest of its kind reported to date.

Primary cutaneous Hodgkin-like polymorphic post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is an uncommon complication after solid-organ transplants and hematopoietic stem cell transplants. Isolated involvement of the skin without systemic involvement in PTLD is extremely rare. Primary cutaneous PTLD is generally categorized as either cutaneous T-cell lymphoma or cutaneous B-cell lymphoma, with variable Epstein-Barr virus (EBV) positivity. Herein, we describe an exceedingly uncommon case of a primary cutaneous Hodgkin-like polymorphic PTLD. A man in his 60s, with a history of kidney transplant, presented with a 5-week history of two indurated plaques. Clinical, histologic and immunohistochemical findings were consistent with primary cutaneous Hodgkin-like polymorphic PTLD. Reduction in immunosuppression led to resolution of his lesions. This case highlights a rare case of primary cutaneous Hodgkin-like PTLD and increases awareness of this uncommon post-transplant complication. It also underscores the importance of collaboration between dermatology, hematology, dermatopathology and hematopathology in order to diagnose challenging cases.

Parathyroid carcinoma with intracranial metastasis at diagnosis in a patient with uncontrolled hypercalcemia.

Parathyroid carcinoma is an uncommon malignancy and a rare cause of primary hyperparathyroidism. Although this tumor is capable of metastasis, metastatic disease is very uncommon intracranially, with only seven cases reported in the literature. When intracranial metastases occur, they typically present months to years following the diagnosis of the primary tumor with hypercalcemia refractory to medical conservative treatment. Aggressive surgical resection of all metastases is necessary for control of the disease. We report a case of metastatic parathyroid carcinoma with two intracranial metastatic foci (in the left frontal lobe and left cerebellar hemisphere) identified at the time of the primary tumor diagnosis in a patient who presented with symptomatic hypercalcemia.

Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

Loss of glutathione S-transferase (GST) mu phenotype in colorectal adenocarcinomas from patients with a GSTM1 positive genotype.

Glutathione S-transferase (GST) mu phenotype was assessed in colon tissue from patients with ulcerative colitis and colorectal neoplasms that were positive for GSTM1 genotype. GST mu protein (enzyme linked immunosorbent assay) was absent in 2/9 unaffected colon tissue (22.3%), 4/13 tissues with chronic ulcerative colitis (CUC) (30.7%), 4/11 adenomas (36.4%) and 7/14 adenocarcinomas (50.0%; P