Mitochondrial Heteroplasmy Shifting as a Potential Biomarker of Cancer Progression

Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.

Inchworming After Tagging the Ball Proves an Efficient Method for Opening a Completion Isolation Valve with Electric-Line Powered Shifting Tool in Deepwater Gulf of Mexico: A Case Study

An intervention operation in the Gulf of Mexico used a novel method with an electric-line powered shifting tool to reliably locate and latch onto the shifting profile of the intended completion isolation valve successfully completing the shifting operation. Locating and latching onto the lower shifting profile of a completion isolation valve is often a challenging operation with slickline or conventional electric-line shifting tools. It relies on the weight of the downhole tool to provide the downward force to drive the shifter to latch onto the shifting profile. Numerous parameters such as the well deviation, the friction force of the shifter keys with the tubing, and the pull from the cable highly affect this downward force. Accurate positioning of the downhole tool with respect to the completion is even more challenging in deep water wells because the long cable stretch can result in several feet of uncertainty. The novel method used in this operation consisted of using the shifter, linear actuator, and anchor modules to move in an inchworm motion after tagging the closed ball valve. The tag was used as a reference point to accurately locate the position of the shifter with respect to the valve opening shifting profile. While moving toward the profile, the position of the shifter was maintained at all times using the accurate linear position measurement of the tool. The linear actuator has a limited stroke, but it can be compounded to achieve a much longer measurement. Because the tag position of the shifter was only a few linear actuator strokes away from the opening profile, the operation was extremely efficient. The intervention operation was successfully completed in a few hours using this method. The signals were measured downhole and reported in real time to surface, enabling accurate monitoring of the progress and indicating the position of the tool with respect to the valve opening profile at all times. While moving toward the profile after tagging the ball, the shifter was used to probe for diameter changes. This measurement provided an additional confirmation of the position of the shifter, which was able to sense passing through the profile. Finally, after passing the profile and reversing direction, a controlled increase in the linear actuator axial force confirmed the latch onto the opening profile. This seek method enabled latching onto the opening profile and confirmed without doubt that the shifter keys were engaged in the profile before proceeding to increase the forces to shift the ball open. While the ball valve was shifted open, the downhole measurements recorded an axial force vs. displacement footprint that is characteristic of the opening of the ball valve, giving confirmation that the operation was successfully completed without having to physically pass through the ball valve to confirm. This was the first time that this method, consisting of moving in an inchworm motion after tagging the ball, had been used for locating and latching onto the shifting profile of a completion isolation valve. This novel method eliminated uncertainty from conventional methods that use the cable overpull and head tension as a latch indicator.

Emission Aware Eco-Driving on Country Roads

Eco-driving is a way to improve performance — mainly energy consumption — of road vehicles by computing an optimal speed and gear shifting profile based on vehicle data and road profile, e.g. slopes or speed limits. It mainly focuses on long haul scenarios such as highways, considering longitudinal movement only. Lateral acceleration of a vehicle is a critical quantity both in terms of comfort and safety, but its impact on fuel consumption or emissions is rarely considered or believed to be limited [1], as it does not affect directly the operating point of the engine. However, on country roads which usually present much stronger curvatures, lateral acceleration may be a critical constraint. In this paper, the impact of lateral acceleration limits on optimal solutions to multi-objective eco-driving is investigated. It is found that it may play an even more critical role than longitudinal acceleration with respect to fuel consumption and NOx emission. As a consequence, the choice of limits to lateral acceleration on curvy roads should be set very carefully in order to achieve a balance between energy saving, drivers comfort and travel time. The results of this work are validated on a high-feasibility Hardware-in-the-loop (HIL) system calibrated with data from Real Driving Emissions tests.

New Wave Cinéaste to Digital Gleaner

This chapter highlights Agnès Varda's place in New Wave cinema history. It illustrates how Varda's ever-shifting profile has evolved from avant-garde precursor to the “grandmother” of the New Wave. Yet what remains consistent here is her commitment to storytelling that foregrounds isolated people in distinctive settings in both documentary and fiction films. Varda's ongoing journey reveals an artist who needs to create, who is in motion and incapable of ceasing, making do with whatever resources are available to her (including harnessing that creativity toward visual arts and installation when funds for filmmaking were scarce), remaining eminently pragmatic even when attacking new challenges.

Increasing Operational Efficiency in Extended Reach, Offshore Wells – A Case Story from Middle East

ABSTRACT Objective A case story from ME will be presented covering an extreme extended reach, offshore well. Any increase to operating efficiency can save time and increase production. In this case story two SSD's were opened in a single run on e-line, an outstanding achievement due to the ID restrictions and extended reach of the well. The paper will discuss the planning, the operation, the achievements and the lessons learned. Methods, Procedures, Process This well was recently worked over, retrieval and new installation of upper and lower completion. Due to the well going on total losses during the workover, a closed system was deployed to enable the operator to set the hydraulic packers. The packer is utilized for isolation between two zones, with each zone having two SSD's in which one SSD per zone was required to be opened to allow access to the formation. From day one of planning the primary solution for this intervention was an electric over hydraulic toolstring made up of five tools, a 218 electric release device, 218 CCL for correlation, a 218 tractor for conveyance, a 218 stroker for the mechanical manipulation and a 218 key to address the shifting profile in the SSD (toolstring). A slimhole toolstring was required due to the packer ID of 2.81" The operator was using the service provider for other interventions on this workover campaign and decided to challenge them with opening two SSD's in one run while not shifting the adjacent SSD's. The challenging underlying economics of the industry today has created a powerful driver for operators to find more efficient, cost effective and safer intervention methodologies. The operation covered in this case provided just such improvements to the client: by utilizing electric line intervention tools the operator negated the requirement for a large footprint coiled tubing intervention. Results, Observations, Conclusions A System Integration Test (SIT) was completed onshore prior to mobilization, where multiple shifts were successfully executed on a 90° deviated pipe using a single set of shifting key pads. Test results were then repeated offshore, completing two interventions in a single run. The SSD's were successfully opened at ~12,000 ft MDRT and ~8,000 ft MDRT, respectively while leaving the two adjacent SSD's in the closed position. Results, client objective was 100% achieved using only electric line, enabling the client to move forward with similar well designs having the confidence that a safe, reliable electric line solution is locally available. Additional results include reduced HSE risks as the e-line approach eliminated the use of a heavier CTU. Further contributing to the HSE benefits on this operation, only 6 persons were needed on site and no heavy lifts were required. The paper will also cover some lessons learned as debris in the profile and tubing caused some challenges. Novel/Additive Information This operation shows how the industry is constantly trying to improve on existing methods in order to be more efficient, safe and cost effective.