Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.

Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer. 

Consensus, debate, and prospective on pancreatic cancer treatments

Power-electronic-based grid emulators are emerging as a promising way to test the grid-code compliance of renewable energy resources. Yet, the ever-increasing power and voltage levels of device under test pose new requirements and challenges to power-electronic-based grid emulators. This paper first gives an overview of testing capability requirements based on the recent grid codes and standards, then discusses the resulted dynamic interactions and solutions for power-electronic-based grid emulators. Perspectives on the open issues and emerging trends of grid emulators are finally shared. 

Medium-Voltage Megawatt Power-Electronic-Based Grid Emulators: Testing Capability Requirements and Dynamics Challenges – A Review

Power-electronic-based grid emulators (GEs) emerge as a favorable method for testing grid-code compliances of wind turbines (WTs), thanks to their full controllability and improved efficiency. To accommodate the increasing power and voltage levels of WTs, scalability becomes a critical requirement for the topologies of converter-based GEs. This paper identifies first the power rating of future GEs based on the system architecture and the evolution of WTs, followed by evaluating converter topologies of GEs for high scalability. Design considerations of power semiconductor devices, step-up transformers, dc chopper and dc capacitors are also discussed for existing and prospective GEs. 

Power-Hardware Design and Topologies of Converter-Based Grid Emulators for Wind Turbines

Pancreatic cancer represents a formidable challenge in oncology, primarily due to its aggressive nature and limited therapeutic options. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), the main form of pancreatic cancer, remains disappointingly poor with a 5-year overall survival of only 5%. Almost 95% of PDAC patients harbor Kirsten rat sarcoma virus (KRAS) oncogenic mutations. KRAS activates downstream intracellular pathways, most notably the rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling axis. Dysregulation of the RAF/MEK/ERK pathway is a crucial feature of pancreatic cancer and therefore its main components, RAF, MEK and ERK kinases, have been targeted pharmacologically, largely by small-molecule inhibitors. The recent advances in the development of inhibitors not only directly targeting the RAF/MEK/ERK pathway but also indirectly through inhibition of its regulators, such as Src homology-containing protein tyrosine phosphatase 2 (SHP2) and Son of sevenless homolog 1 (SOS1), provide new therapeutic opportunities. Moreover, the discovery of allele-specific small-molecule inhibitors against mutant KRAS variants has brought excitement for successful innovations in the battle against pancreatic cancer. Herein, we review the recent advances in targeted therapy and combinatorial strategies with focus on the current preclinical and clinical approaches, providing critical insight, underscoring the potential of these efforts and supporting their promise to improve the lives of patients with PDAC.

Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives

The modular multilevel converter (MMC)-based grid emulator is recently reported as a promising approach for grid-code compliance testing of next-generation wind turbines. This paper reveals the overvoltage on the submodule (SM) capacitor of the MMC-based grid emulator during the low-voltage ride-through (LVRT) test, and proposes an approach to address such issue. First, a simplified average model is developed to quantify the maximum and minimum SM capacitor voltage during the LVRT test. Then, a SM capacitor energy balancing approach is proposed to mitigate the transient overvoltage, which limits the SM capacitor voltage within 60%~110% of the rated voltage. Simulation results have confirmed the correctness of the theoretical analysis. 

Analysis and mitigation of submodule capacitor overvoltage for MMC-based grid emulator under LVRT test

Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK with a prolonged target residence time (550 min). The first-in-human Phase 1 study of ERAS-007 identified the 250 mg once weekly (QW) schedule for further evaluation based on a manageable toxicity profile and encouraging signs of clinical activity (NCT03415126). Pharmacokinetic (PK) modeling suggests that an alternative intermittent regimen (twice a day, once a week; BID-QW) is expected to have lower peak concentrations (Cmax) and similar overall PK exposures (area under the curve, AUC) compared to QW, which may improve Cmax-driven adverse events (AE) while maintaining comparable efficacy. Optimizing tolerability is particularly beneficial as combination therapies of ERAS-007 with other anti-cancer agents are being pursued. Materials and Methods: HERKULES-1 is a Phase 1b/2 study evaluating ERAS-007 in patients (pts) with metastatic solid tumors refractory to standard therapies (NCT04866134). Primary objectives in Part A (dose escalation) include evaluation of safety and PK characteristics, and determination of the maximum tolerated dose of ERAS-007 administered as monotherapy on a BID-QW schedule. Secondary objectives include evaluation of tolerability and anti-tumor activity. ERAS-007 was administered at increasing dose levels of 50, 100, and 125 mg on a BID-QW schedule. Results: As of the 23 May 2022 data cutoff, 23 pts were enrolled at doses of 50 (n = 4), 100 (n = 11), and 125 mg (n = 8) BID-QW. A maximum administered dose of 125 mg BID-QW was achieved; no DLTs were observed at any dose level. All grade treatment related adverse events (TRAE) occurring in ≥20% of the BID-QW treated pts included nausea (52.2%), eye disorders (52.2%), skin rash (43.5%), fatigue (39.1%), vomiting (30.4%), and diarrhea (21.7%). These AEs were mostly Grades 1 and 2. Grade ≥3 TRAEs occurring in ≥10% of patients were eye disorders (13.0%). ERAS-007 administered as a BID-QW schedule exhibited lower peak-to-trough fluctuations compared to a QW regimen. An unconfirmed partial response was observed in a patient with KRAS G12 V mutated pancreatic ductal adenocarcinoma. Updated data on safety, PK, and dose selection for ongoing studies with ERAS-007 combinations will be presented. Conclusions: ERAS-007 is a potent and selective oral inhibitor of ERK1/2 with a prolonged target residence time. Intermittent dosing on a BID-QW schedule exhibited favorable PK characteristics with lower Cmax and similar overall PK exposure (AUC) compared to QW dosing and demonstrated a monitorable and manageable AE profile consistent with the underlying mechanism of action. This novel regimen offers an alternative schedule for combination development. Conflict of interest: Ownership: Xiaoying Chen, Jennifer Gordon, Zhengrong Li, Moshe Reiss, Sachin Pai Corporate-sponsored Research:Judy Wang, Melissa Johnson, Minal Barve, Meredith Pelster, Gerald Falchook, Anthony Tolcher 

Preliminary results from HERKULES-1: a phase 1b/2, open-label, multicenter study of ERAS-007, an oral ERK1/2 inhibitor, in patients with advanced or metastatic solid tumors

Feasibility of output-only damage detection method using response of a vehicle moving on a bridge

The proceedings of the conference can be downloaded from: http://www.polyu.edu.hk/fclu/ipc2011/download.html

Damage detection of girder bridges from dynamic response of a moving vehicle

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Analysis and mitigation of submodule capacitor overvoltage for MMC-based grid emulator under LVRT test

Preliminary results from HERKULES-1: a phase 1b/2, open-label, multicenter study of ERAS-007, an oral ERK1/2 inhibitor, in patients with advanced or metastatic solid tumors

Feasibility of output-only damage detection method using response of a vehicle moving on a bridge

Damage detection of girder bridges from dynamic response of a moving vehicle