MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.

MDM2 and MDM4 are key regulators of p53 and function as oncogenes when aberrantly expressed. MDM2 and MDM4 partner to suppress p53 transcriptional transactivation and polyubiquitinate p53 for degradation. The importance of MDM2 E3-ligase-mediated p53 regulation remains controversial. To resolve this, we generated mice with an Mdm2 L466A mutation that specifically compromises E2 interaction, abolishing MDM2 E3 ligase activity while preserving its ability to bind MDM4 and suppress p53 transactivation. Mdm2L466A/L466A mice exhibit p53-dependent embryonic lethality, demonstrating MDM2 E3 ligase activity is essential for p53 regulation in vivo. Unexpectedly, cells expressing Mdm2L466A manifest cell cycle G2-M transition defects and increased aneuploidy even in the absence of p53, suggesting MDM2 E3 ligase plays a p53-independent role in cell cycle regulation and genome integrity. Furthermore, cells bearing the E3-dead MDM2 mutant show aberrant cell cycle regulation in response to DNA damage. This study uncovers an uncharacterized role for MDM2's E3 ligase activity in cell cycle beyond its essential role in regulating p53's stability in vivo.

Correction: MDM2 E3 ligase activity is essential for p53 regulation and cell cycle integrity.

[This corrects the article DOI: 10.1371/journal.pgen.1010171.].

Relativistic gas: Lorentz-invariant distribution for the velocities.

In 1911, Jüttner proposed the generalization, for a relativistic gas, of the Maxwell-Boltzmann distribution of velocities. Here, we want to discuss, among others, the Jüttner probability density function (PDF). Both the velocity space and, consequently, the momentum space are not flat in special relativity. The velocity space corresponds to the Lobachevsky one, which has a negative curvature. This curvature induces a specific power for the Lorentz factor in the PDF, affecting the Jüttner normalization constant in one, two, and three dimensions. Furthermore, Jüttner distribution, written in terms of a more convenient variable, the rapidity, presents a curvature change at the origin at sufficiently high energy, which does not agree with our computational dynamics simulations of a relativistic gas. However, in one dimension, the rapidity satisfies a simple additivity law. This allows us to obtain, through the central limit theorem, a new, Lorentz-invariant, PDF whose curvature at the origin does not change for any energy value and which agrees with our computational dynamics simulations data. Also, we perform extensive first-principle simulations of a one-dimensional relativistic gas constituted by light and heavy particles.

Acute fulminant amoebic colitis: A Case report.

Amoebiasis is a parasitic infection that represents a public health problem in developing countries including Asia and Latin America where it is endemic (1000-5000 cases/100,000 habitants/year). The majority of patients have an asymptomatic course; however, 10% of patients develop complications with high morbidity and mortality, such as colonic perforation or fulminant amoebic colitis. We report a case in which a 73-year-old female presented with an acute abdomen that was initially attributed to a bowel obstruction that rapidly progressed to fulminant colitis with bowel perforation requiring total colectomy. Pre-surgical endoscopic histopathological examination revealed findings suggestive of Entamoeba histolytica trophozoites that were later confirmed in the colon post-surgical specimen leading to a diagnosis of fulminant amoebic colitis. This atypical presentation of amoebiasis, further expands the already broad differential diagnosis of acute abdominal pathology in the elderly population. A high index of suspicion is required for its prompt treatment and to prevent life-threatening complications.

Augmenting antibody response to EGF-depleting immunotherapy: Findings from a phase I trial of CIMAvax-EGF in combination with nivolumab in advanced stage NSCLC.

Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Increased ß-adrenergic receptor (ß-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly ß2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective ß-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. RESULTS: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. CONCLUSIONS: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

Wernicke Encephalopathy After Sleeve Gastrectomy.

Wernicke encephalopathy (WE) is a rare and serious complication of obesity surgery. This is a report of one case of WE after a sleeve gastrectomy. The diagnosis is primarily clinical; the persistent and prolonged vomiting, and noncompliance to vitamin intake are two major risk factors to develop WE. It is especially important to rule out for stenosis or obstructions of the upper digestive tract after surgery. MRI is useful with high specificity to support the diagnosis as in our case, and discard other causes. Treatment should not be delayed. The outcome of WE is not always predictable. The full recovery is not always achieved, but there is improvement over the time as in this case.

DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11.

MAGEA11 is a cancer germline (CG) antigen and androgen receptor co-activator. Its expression in cancers other than prostate, and its mechanism of activation, has not been reported. In silico analyses reveal that MAGEA11 is frequently expressed in human cancers, is increased during tumor progression, and correlates with poor prognosis and survival. In prostate and epithelial ovarian cancers (EOC), MAGEA11 expression was associated with promoter and global DNA hypomethylation, and with activation of other CG genes. Pharmacological or genetic inhibition of DNA methyltransferases (DNMTs) and/or histone deacetylases (HDACs) activated MAGEA11 in a cell line specific manner. MAGEA11 promoter activity was directly repressed by DNA methylation, and partially depended on Sp1, as pharmacological or genetic targeting of Sp1 reduced MAGEA11 promoter activity and endogenous gene expression. Importantly, DNA methylation regulated nucleosome occupancy specifically at the -1 positioned nucleosome of MAGEA11. Methylation of a single Ets site near the transcriptional start site (TSS) correlated with -1 nucleosome occupancy and, by itself, strongly repressed MAGEA11 promoter activity. Thus, DNA methylation regulates nucleosome occupancy at MAGEA11, and this appears to function cooperatively with sequence-specific transcription factors to regulate gene expression. MAGEA11 regulation is highly instructive for understanding mechanisms regulating CG antigen genes in human cancer.