Modular multilevel converter-based microgrid : a critical review

Recently, the Modular Multilevel Converter (MMC) has drawn significant attention due to its diverse merits and its applicability to a wide range of medium to high-power applications. The growing interest in the MMC can be attributed to its attractive features such as modularity, reliability, and high voltage capability. Significant research has been conducted on the MMC over the last few years to develop its operation and control in various applications. However, the application of MMCs in microgrids remains a largely unexplored topic. Therefore, this paper aims to address this research gap by offering an in-depth review of the latest developments concerning circuit topologies, control schemes, and fault-tolerance strategies of MMC within microgrid applications. This comprehensive review not only provides a synthesized overview of the current state of the art but also paves the way for future investigations in this promising field. The outcomes from this study are expected to stimulate further advancements in MMC applications in microgrid systems, thus contributing to the continuous improvement and evolution of microgrids.University of Sharjahhttps://ieeexplore.ieee.org/xpl/RecentIssue.jsp?punumber=6287639Electrical, Electronic and Computer Engineerin

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Hypertensive Crisis in a Patient With a Functioning Mesenteric Paraganglioma: Dramatic Response to Octreotide Treatment

Background/Objective: To report a dramatic and immediate clinical and biochemical response during treatment with octreotide in a patient with a functioning mesenteric paraganglioma (PGL). Case Report: A 44-year-old woman was admitted with a severe hypertensive crisis and a blood pressure reaching 260/150 mm Hg. She was 2 months postpartum and had been previously diagnosed with pre-eclampsia. Secondary hypertension was suspected. This was confirmed by finding a 6 × 5-cm2 retroperitoneal mass located using 68-Gallium DOTA–octreotate positron emission tomography/computed tomography and a grossly elevated plasma catecholamine level of 93 000 pmol/L (normal reference range: 650-2433 pmol/L). Treatment was immediately started with high doses of long- and short-acting octreotide. After 6 weeks and before surgery, the patient was normotensive, with a blood pressure of 120/70 mm Hg and a norepinephrine level of 6000 pmol/L. The tumor resection was uneventful, and histology confirmed the diagnosis. Following the surgery, the patient remained normotensive without any medications. Discussion: PGLs and pheochromocytomas are neuroendocrine tumors, and most have receptors for octreotide. This case and another patient previously reported responded dramatically to treatment with a high dose of octreotide. Earlier reports of patients failing to respond are likely to have been the result of using a smaller octreotide dose. Conclusion: We conclude that high doses of short- and long-acting octreotide are valuable in severely hypertensive patients. Our experience suggests that octreotide is of value in other patients with PGLs and pheochromocytomas. The response is rapid, sustained, effective, and with minimal reported side effects. To the best of our knowledge, this is the first report of a hypertensive crisis in a functional mesenteric PGL

Tracking the Evolution of Non-Small-Cell Lung Cancer.

BACKGROUND Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10(-4)), which remained significant in multivariate analysis. CONCLUSIONS Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .)