Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence.

There is a growing body of literature demonstrating the importance of T cell exhaustion in regulating and shaping immune responses to pathogens and cancer. Simultaneously, the parallel development of therapeutic antibodies targeting inhibitory molecules associated with immune exhaustion (such as PD-1, but also TIGIT, and LAG-3) has led to a revolution in oncology with dramatic benefits in a growing list of solid and hematologic malignancies. Given this success in reinvigorating exhausted T cells and the related anti-tumor effects, there are increasing efforts to apply immune checkpoint blockade to other exhausted immune cells beyond T cells. One approach involves the reinvigoration of "exhausted" NK cells, a non-T, non-B lymphoid cell of the innate immune system. However, in contrast to the more well-defined and established molecular, genetic, and immunophenotypic characteristics of T cell exhaustion, a consensus on the defining functional and phenotypic features of NK "exhaustion" is less clear. As is well-known from T cell biology, separate and distinct molecular and cellular processes including senescence, anergy and exhaustion can lead to diminished immune effector function with different implications for immune regulation and recovery. For NK cells, it is unclear if exhaustion, anergy, and senescence entail separate and distinct entities of dysfunction, though all are typically characterized by decreased effector function or proliferation. In this review, we seek to define these distinct spheres of NK cell dysfunction, analyzing how they have been shown to impact NK biology and clinical applications, and ultimately highlight key characteristics in NK cell function, particularly in relation to the role of "exhaustion.

Characterization and Potential Applications of Dog Natural Killer Cells in Cancer Immunotherapy.

Natural killer (NK) cells of the innate immune system are a key focus of research within the field of immuno-oncology based on their ability to recognize and eliminate malignant cells without prior sensitization or priming. However, barriers have arisen in the effective translation of NK cells to the clinic, in part because of critical species differences between mice and humans. Companion animals, especially dogs, are valuable species for overcoming many of these barriers, as dogs develop spontaneous tumors in the setting of an intact immune system, and the genetic and epigenetic factors that underlie oncogenesis appear to be similar between dogs and humans. Here, we summarize the current state of knowledge for dog NK cells, including cell surface marker phenotype, key NK genes and genetic regulation, similarities and differences of dog NK cells to other mammals, especially human and mouse, expression of canonical inhibitory and activating receptors, ex vivo expansion techniques, and current and future clinical applications. While dog NK cells are not as well described as those in humans and mice, the knowledge of the field is increasing and clinical applications in dogs can potentially advance the field of human NK biology and therapy. Better characterization is needed to truly understand the similarities and differences of dog NK cells with mouse and human. This will allow for the canine model to speed clinical translation of NK immunotherapy studies and overcome key barriers in the optimization of NK cancer immunotherapy, including trafficking, longevity, and maximal in vivo support

Increased Rates of Prolonged Length of Stay, Readmissions, and Discharge to Care Facilities among Postoperative Patients with Disseminated Malignancy: Implications for Clinical Practice.

BackgroundThe impact of surgery on end of life care for patients with disseminated malignancy (DMa) is incompletely characterized. The purpose of this study was to evaluate postoperative outcomes impacting quality of care among DMa patients, specifically prolonged length of hospital stay, readmission, and disposition.MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for years 2011-2012. DMa patients were matched to non-DMa patients with comparable clinical characteristics and operation types. Primary hepatic operations were excluded, leaving a final cohort of 17,972 DMa patients. The primary outcomes were analyzed using multivariate Cox regression models.ResultsDMa patients represented 2.1% of all ACS-NSQIP procedures during the study period. The most frequent operations were bowel resections (25.3%). Compared to non-DMa matched controls, DMa patients had higher rates of postoperative overall morbidity (24.4% vs. 18.7%, p<0.001), serious morbidity (14.9% vs. 12.0%, p<0.001), mortality (7.6% vs. 2.5%, p<0.001), prolonged length of stay (32.2% vs. 19.8%, p<0.001), readmission (15.7% vs. 9.6%, p<0.001), and discharges to facilities (16.2% vs. 12.9%, p<0.001). Subgroup analyses of patients by procedure type showed similar results. Importantly, DMa patients who did not experience any postoperative complication experienced significantly higher rates of prolonged length of stay (23.0% vs. 11.8%, p<0.001), readmissions (10.0% vs. 5.2%, p<0.001), discharges to a facility (13.2% vs. 9.5%, p<0.001), and 30-day mortality (4.7% vs. 0.8%, p<0.001) compared to matched non-DMa patients.ConclusionSurgical interventions among DMa patients are associated with poorer postoperative outcomes including greater postoperative complications, prolonged length of hospital stay, readmissions, disposition to facilities, and death compared to non-DMa patients. These data reinforce the importance of clarifying goals of care for DMa patients, especially when acute changes in health status potentially requiring surgery occur

Criminal narrative experience: relating emotions to offence narrative roles during crime commission

A neglected area of research within criminality has been that of the experience of the offence for the offender. The present study investigates the emotions and narrative roles that are experienced by an offender while committing a broad range of crimes and proposes a model of Criminal Narrative Experience (CNE). Hypotheses were derived from the Circumplex of Emotions (Russell, 1997), Frye (1957), Narrative Theory (McAdams, 1988) and its link with Investigative Psychology (Canter, 1994). The analysis was based on 120 cases. Convicted for a variety of crimes, incarcerated criminals were interviewed and the data were subjected to Smallest Space Analysis (SSA). Four themes of Criminal Narrative Experience (CNE) were identified: Elated Hero, Calm Professional, Distressed Revenger and Depressed Victim in line with the recent theoretical framework posited for Narrative Offence Roles (Youngs & Canter, 2012). The theoretical implications for understanding crime on the basis of the Criminal Narrative Experience (CNE) as well as practical implications are discussed

Offenders' Crime Narratives across Different Types of Crimes

The current study explores the roles offenders see themselves playing during an offence and their relationship to different crime types. One hundred and twenty incarcerated offenders indicated the narrative roles they acted out whilst committing a specific crime they remembered well. The data were subjected to Smallest Space Analysis (SSA) and four themes were identified: Hero, Professional, Revenger and Victim in line with the recent theoretical framework posited for Narrative Offence Roles (Youngs & Canter, 2012). Further analysis showed that different subsets of crimes were more like to be associated with different narrative offence roles. Hero and Professional were found to be associated with property offences (theft, burglary and shoplifting), drug offences and robbery and Revenger and Victim were found to be associated with violence, sexual offences and murder. The theoretical implications for understanding crime on the basis of offenders' narrative roles as well as practical implications are discussed

Locally Advanced Spiroadenocarcinoma in the Regional Axilla of a Breast Cancer Patient: Hallmarks of Definitive Diagnosis and Management.

Eccrine spiroadenocarcinoma is an extremely rare malignant eccrine gland tumor which may masquerade as other more common malignancies such as poorly differentiated squamous carcinoma or metastatic breast cancer. We report a case of an ulcerated axillary skin lesion with bulky adenopathy in a 77 year-old female with a prior history of ipsilateral triple negative breast carcinoma. The clear transition of benign spiradenoma to malignant carcinoma was essential to establishing a definitive diagnosis and treatment plan

Delayed phlegmon with gallstone fragments masquerading as soft tissue sarcoma.

Complications from lost gallstones after cholecystectomy are rare but varied from simple perihepatic abscess to empyema and expectoration of gallstones. Gallstone complications have been reported in nearly every organ system, although reports of malignant masquerade of retained gallstones are few. We present the case of an 87-year-old woman with a flank soft tissue tumor 4 years after laparoscopic cholecystectomy. The initial clinical, radiographic and biopsy findings were consistent with soft tissue sarcoma (STS), but careful review of her case in multidisciplinary conference raised the suspicion for retained gallstones rather than STS. The patient was treated with incisional biopsy/drainage of the mass, and gallstones were retrieved. The patient recovered completely without an extensive resectional procedure, emphasizing the importance of multidisciplinary sarcoma care to optimize outcomes for potential sarcoma patients

Application of High-precision Timing Systems to Distributed Survey Systems

In any hydrographic survey system that consists of more than one computer, one of the most difficult integration problems is to ensure that all components maintain a coherent sense of time. Since virtually all modern survey systems are of this type, timekeeping and synchronized timestamping of data as it is created is of significant concern. This paper describes a method for resolving this problem based on the IEEE 1588 Precise Time Protocol (PTP) implemented by hardware devices, layered with some custom software called the Software Grandmaster (SWGM) algorithm. This combination of hardware and software maintains a coherent sense of time between multiple ethernet-connected computers, on the order of 100 ns (rms) in the best case, of the timebase established by the local GPS-receiver clock. We illustrate the performance of this techniques in a practical survey system using a Reson 7P sonar processor connected to a Reson 7125 Multibeam Echosounder (MBES), integrated with an Applanix POS/MV 320 V4 and a conventional data capture computer. Using the timing capabilities of the PTP hardware implementations, we show that the timepieces achieve mean (hardware based) synchronization and timestamping within 100-150 ns (rms), and that the data created at the Reson 7P without hardware timestamps has a latency variability of 28 µs (rms) due to software constraints within the capture system. This compares to 288 ms (rms) using Reson’s standard hybrid hardware/software solution, and 13.6 ms (rms) using a conventional single-oscillator timestamping model

Converting Evidence Into Data: The Use Of Law Enforcement Archives As Unobtrusive Measurement

The newly emerging area of Investigative Psychology provides a behavioural science basis for crime detection by examining investigative processes and criminal behaviour. It draws upon a range of material collected by law enforcement agencies that is not widely utilized in the social sciences. This may be regarded as a form of non-reactive, unobtrusive data that has many of the advantages originally promoted by Webb, Campbell, Schwartz and Sechrest (1966) and more recently explored by Lee (2000). The value of such data, derived from police sources, has been demonstrated in a variety of Investigative Psychology studies. However, law enforcement material is not usually collected as data but rather as evidence. Consideration is therefore given to how to address the challenges this poses. The unobtrusive measures derived from police investigations provide a different perspective on crime and other aspects of human actions from that based on more conventional sources of data such as questionnaires and interviews. To assist in the effective use of measures derived from police information a framework for considering this material is proposed reflecting the range of sources of measures that Lee (2000) identified; personal records, running records, physical traces, and simple observation. As in other areas, close attention to the methods of collecting such material can considerably improve its utility. The measures being utilized in Investigative Psychology therefore offer some fruitful directions for other areas of social science research. Development of these measures can also improve the effectiveness of criminal investigations