Neoadjuvant personalized cancer vaccines: the final frontier?

INTRODUCTION: Clinical trials of personalized cancer vaccines have shown that on-demand therapies that are manufactured for each patient, result in activated T cell responses against individual tumor neoantigens. However, their use has been traditionally restricted to adjuvant settings and late-stage cancer therapy. There is growing support for the implementation of PCV earlier in the cancer therapy timeline, for reasons that will be discussed in this review. AREAS COVERED: The efficacy of cancer vaccines may be to some extent dependent on treatment(s) given prior to vaccine administration. Tumors can undergo radical immunoediting following treatment with immunotherapies, such as checkpoint inhibitors, which may affect the presence of the very mutations targeted by cancer vaccines. This review will cover the topics of neoantigen cancer vaccines, tumor immunoediting, and therapy timing. EXPERT OPINION: Therapy timing remains a critical topic to address in optimizing the efficacy of personalized cancer vaccines. Most personalized cancer vaccines are being evaluated in late-stage cancer patients and after treatment with checkpoint inhibitors, but they may offer a greater benefit to the patient if administered in earlier clinical settings, such as the neoadjuvant setting, where patients are not facing T cell exhaustion and/or a further compromised immune system.

A Mouse Holder for Awake Functional Imaging in Unanesthetized Mice: Applications in 31P Spectroscopy, Manganese-Enhanced Magnetic Resonance Imaging Studies, and Resting-State Functional Magnetic Resonance Imaging.

Anesthesia is often used in preclinical imaging studies that incorporate mouse or rat models. However, multiple reports indicate that anesthesia has significant physiological impacts. Thus, there has been great interest in performing imaging studies in awake, unanesthetized animals to obtain accurate results without the confounding physiological effects of anesthesia. Here, we describe a newly designed mouse holder that is interfaceable with existing MRI systems and enables awake in vivo mouse imaging. This holder significantly reduces head movement of the awake animal compared to previously designed holders and allows for the acquisition of improved anatomical images. In addition to applications in anatomical T2-weighted magnetic resonance imaging (MRI), we also describe applications in acquiring 31P spectra, manganese-enhanced magnetic resonance imaging (MEMRI) transport rates and resting-state functional magnetic resonance imaging (rs-fMRI) in awake animals and describe a successful conditioning paradigm for awake imaging. These data demonstrate significant differences in 31P spectra, MEMRI transport rates, and rs-fMRI connectivity between anesthetized and awake animals, emphasizing the importance of performing functional studies in unanesthetized animals. Furthermore, these studies demonstrate that the mouse holder presented here is easy to construct and use, compatible with standard Bruker systems for mouse imaging, and provides rigorous results in awake mice.

Development of a potent Zika virus vaccine using self-amplifying messenger RNA.

Zika virus (ZIKV) is the cause of a pandemic associated with microcephaly in newborns and Guillain-Barre syndrome in adults. Currently, there are no available treatments or vaccines for ZIKV, and the development of a safe and effective vaccine is a high priority for many global health organizations. We describe the development of ZIKV vaccine candidates using the self-amplifying messenger RNA (SAM) platform technology delivered by cationic nanoemulsion (CNE) that allows bedside mixing and is particularly useful for rapid responses to pandemic outbreaks. Two immunizations of either of the two lead SAM (CNE) vaccine candidates elicited potent neutralizing antibody responses to ZIKV in mice and nonhuman primates. Both SAM (CNE) vaccines protected these animals from ZIKV challenge, with one candidate providing complete protection against ZIKV infection in nonhuman primates. The data provide a preclinical proof of concept that a SAM (CNE) vaccine candidate can rapidly elicit protective immunity against ZIKV.

[Effectiveness of Health and Safety at Work Services (PSAL) in reducing occupational injuries in Lombardy Region]. / Efficacia dei Servizi di Prevenzione e Sicurezza negli Ambienti di Lavoro (Servizi PSAL) neella riduzione degli infortune professionali in Regione Lombardia.

INTRODUCTION: In recent years, Italy has seen a reduction in workplace accidents due to several factors, including the controls carried out by the Health and Safety at Work Services (PSAL) of the Local Health Units (ATS). OBJECTIVE: To verify the contribution of PSAL Services to injury reduction. In particular, to identify the existence of a difference between incidence rates of accidents in companies before and after inspections and possible variations in rates between inspected and non-inspected companies. METHODS: We analyzed data of the activities carried out by the PSAL Services of the Lombardy Region in the system I.M.Pre.S@ (Computerization and Health Prevention Monitoring) in the period 2010-2015, together with data from the Regional Accident Database of the National Institute for Insurance against Accidents at Work (INAIL). The "difference in difference" (DID) method was used to evaluate the different effect on inspected and non-inspected industries. RESULTS: Between the pre- and post-vigilance periods, inspected companies showed a greater reduction either of total injury rates (DID=-2.7 per 1000 worker-years; 90% confidence interval (CI): -4.1; -1.3) or of severe injury rates (DID=-1.1; 90% CI: -1.7; -0.5). These effects were visible in the majority of ATS and occupational sectors. CONCLUSIONS: This study, made possible by a valid and efficient regional data tracking system, has shown the positive effect of the PSAL prevention actions on the frequency of both total and severe injuries.

Metformin-Induced Hemolytic Anemia in a Patient With Glucose-6-Phosphate Dehydrogenase Deficiency.

Metformin, an oral antidiabetic agent, is considered the preferred first-line therapy for patients with type II diabetes. Between 2010 and 2012, it has been estimated that 14 million Americans were administered an oral antidiabetic agent, suggesting the extensive use of metformin among the diabetic population. There have been few case reports implicating metformin in causing hemolytic anemia. We present a case of a 53-year-old white male who developed hemolytic anemia after the initiation of treatment with metformin 500 mg twice daily. The patient experienced a 1.5 g/dL decrease in hemoglobin from baseline and a 2.8 mg/dL increase in total bilirubin within 1 day of treatment. Laboratory results confirmed that the patient was also glucose-6-phosphate dehydrogenase deficient. The hemolytic anemia resolved on discontinuation of metformin. Although this adverse effect seems to be rare, it is important to consider its seriousness. Clinicians should be advised to closely monitor patients newly started on metformin.