An Exceptional Response to Dostarlimab in Mismatch Repair Deficient, Microsatellite Instability-High and Platinum Refractory Endometrial Cancer

Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency

CDKN1B mutation and copy number variation are associated with tumor aggressiveness in luminal breast cancer

The CDKN1B gene, encoding for the CDK inhibitor p27kip1, is mutated in defined human cancer subtypes, including breast, prostate carcinomas and small intestine neuroendocrine tumors. Lessons learned from small intestine neuroendocrine tumors suggest that CDKN1B mutations could be subclonal, raising the question of whether a deeper sequencing approach could lead to the identification of higher numbers of patients with mutations. Here, we addressed this question and analyzed human cancer biopsies from breast (n = 396), ovarian (n = 110) and head and neck squamous carcinoma (n = 202) patients, using an ultra-deep sequencing approach. Notwithstanding this effort, the mutation rate of CDKN1B remained substantially aligned with values from the literature, showing that essentially only hormone receptor-positive breast cancer displayed CDKN1B mutations in a relevant number of cases (3%). However, the analysis of copy number variation showed that another fraction of luminal breast cancer displayed loss (8%) or gain (6%) of the CDKN1B gene, further reinforcing the idea that the function of p27kip1 is important in this type of tumor. Intriguingly, an enrichment for CDKN1B alterations was found in samples from premenopausal luminal breast cancer patients (n = 227, 4%) and in circulating cell-free DNA from metastatic luminal breast cancer patients (n = 59, 8.5%), suggesting that CDKN1B alterations could correlate with tumor aggressiveness and/or occur later during disease progression. Notably, many of the identified somatic mutations resulted in p27kip1 protein truncation, leading to loss of most of the protein or of its C-terminal domain. Using a gene-editing approach in a luminal breast cancer cell line, MCF-7, we observed that the expression of p27kip1 truncating mutants that lose the C-terminal domains failed to rescue most of the phenotypes induced by CDKN1B gene knockout, indicating that the functions retained by the C-terminal portion are critical for its role as an oncosuppressor, at least in luminal breast cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

Optimizing C-RAN Backhaul Topologies: A Resilience-Oriented Approach Using Graph Invariants

ABSTRACT: At the verge of the launch of the first commercial fifth generation (5G) system, trends in wireless and optical networks are proceeding toward increasingly dense deployments, supporting resilient interconnection for applications that carry higher and higher capacity and tighter latency requirements. These developments put increasing pressure on network backhaul and drive the need for a re-examination of traditional backhaul topologies. Challenges of impending networks cannot be tackled by star and ring approaches due to their lack of intrinsic survivability and resilience properties, respectively. In support of this re-examination, we propose a backhaul topology design method that formulates the topology optimization as a graph optimization problem by capturing both the objective and constraints of optimization in graph invariants. Our graph theoretic approach leverages well studied mathematical techniques to provide a more systematic alternative to traditional approaches to backhaul design. Specifically, herein, we optimize over some known graph invariants, such as maximum node degree, topology diameter, average distance, and edge betweenness, as well as over a new invariant called node Wiener impact, to achieve baseline backhaul topologies that match the needs for resilient future wireless and optical networks

A feasibility study of powerline communication technology for digital inclusion

ABSTRACT In the current national scene, many actions point at projects of digital inclusion and citizenship. In this context, providing access technologies as a requisite for the implementation of these actions is primordial. In this way, many innovative experiences have been presented in the past few years. This paper presents a study on the Powerline Communication -PLC technology; as a proposal for a feasible access network for Brazilian Amazon. First, the characteristics of the PLC technology are studied from an implanted indoor prototype at Federal University of Pará. The measures used in this prototype serve as input for a created model, from which it is intended to study the system more widely, considering factors such as: scalability, reliability and the physical characteristics

Giant Cell Arteritis Presenting as Small Bowel Infarction

Giant cell arteritis predominantly affects cranial arteries and rarely involves other sites. We report a patient who presented with small bowel obstruction because of infarction from mesenteric giant cell arteritis. She had an unusual cause of her obstruction and a rare manifestation of giant cell arteritis. In spite of aggressive therapy with steroids, she died a month later because of multiple complications. We discuss the diagnosis and management of small bowel obstruction and differential diagnosis of vasculitis of the gastrointestinal tract. We were able to find 11 cases of bowel involvement with giant cell arteritis in the English literature. This case report illustrates that giant cell arteritis can be a cause of small bowel obstruction and bowel infarction. In the proper clinical setting, vasculitides need to be considered early in the differential diagnosis when therapy may be most effective

Delayed Cutaneous Wound Healing and Aberrant Expression of Hair Follicle Stem Cell Markers in Mice Selectively Lacking Ctip2 in Epidermis

This is the publisher’s final pdf. The published article is copyrighted by PLoS and can be found at: http://www.plosone.org/home.action.Background: COUP-TF interacting protein 2 [(Ctip2), also known as Bcl11b] is an important regulator of skin homeostasis, and is overexpressed in head and neck cancer. Ctip2(ep-/-) mice, selectively ablated for Ctip2 in epidermal keratinocytes, exhibited impaired terminal differentiation and delayed epidermal permeability barrier (EPB) establishment during development, similar to what was observed in Ctip2 null (Ctip2(-/-)) mice. Considering that as an important role of Ctip2, and the fact that molecular networks which underlie cancer progression partially overlap with those responsible for tissue remodeling, we sought to determine the role of Ctip2 during cutaneous wound healing. \ud \ud Methodology/Principal Findings: Full thickness excisional wound healing experiments were performed on Ctip2(L2/L2) and Ctip2(ep-/-) animals per time point and used for harvesting samples for histology, immunohistochemistry (IHC) and immunoblotting. Results demonstrated inherent defects in proliferation and migration of Ctip2 lacking keratinocytes during re-epithelialization. Mutant mice exhibited reduced epidermal proliferation, delayed keratinocyte activation, altered cell-cell adhesion and impaired ECM development. Post wounding, Ctip2(ep-/-) mice wounds displayed lack of E-Cadherin suppression in the migratory tongue, insufficient expression of alpha smooth muscle actin (alpha SMA) in the dermis, and robust induction of K8. Importantly, dysregulated expression of several hair follicle (HF) stem cell markers such as K15, NFATc1, CD133, CD34 and Lrig1 was observed in mutant skin during wound repair. \ud \ud Conclusions/Significance: Results confirm a cell autonomous role of keratinocytic Ctip2 to modulate cell migration, proliferation and/or differentiation, and to maintain HF stem cells during cutaneous wounding. Furthermore, Ctip2 in a non-cell autonomous manner regulated granulation tissue formation and tissue contraction during wound closure