Digging Deeper into Precision/Personalized Medicine: Cracking the Sugar Code, the Third Alphabet of Life, and Sociomateriality of the Cell.

Precision/personalized medicine is a hot topic in health care. Often presented with the motto "the right drug, for the right patient, at the right dose, and the right time," precision medicine is a theory for rational therapeutics as well as practice to individualize health interventions (e.g., drugs, food, vaccines, medical devices, and exercise programs) using biomarkers. Yet, an alien visitor to planet Earth reading the contemporary textbooks on diagnostics might think precision medicine requires only two biomolecules omnipresent in the literature: nucleic acids (e.g., DNA) and proteins, known as the first and second alphabet of biology, respectively. However, the precision/personalized medicine community has tended to underappreciate the third alphabet of life, the "sugar code" (i.e., the information stored in glycans, glycoproteins, and glycolipids). This article brings together experts in precision/personalized medicine science, pharmacoglycomics, emerging technology governance, cultural studies, contemporary art, and responsible innovation to critically comment on the sociomateriality of the three alphabets of life together. First, the current transformation of targeted therapies with personalized glycomedicine and glycan biomarkers is examined. Next, we discuss the reasons as to why unraveling of the sugar code might have lagged behind the DNA and protein codes. While social scientists have historically noted the importance of constructivism (e.g., how people interpret technology and build their values, hopes, and expectations into emerging technologies), life scientists relied on the material properties of technologies in explaining why some innovations emerge rapidly and are more popular than others. The concept of sociomateriality integrates these two explanations by highlighting the inherent entanglement of the social and the material contributions to knowledge and what is presented to us as reality from everyday laboratory life. Hence, we present a hypothesis based on a sociomaterial conceptual lens: because materiality and synthesis of glycans are not directly driven by a template, and thus more complex and open ended than sequencing of a finite length genome, social construction of expectations from unraveling of the sugar code versus the DNA code might have evolved differently, as being future-uncertain versus future-proof, respectively, thus potentially explaining the "sugar lag" in precision/personalized medicine diagnostics over the past decades. We conclude by introducing systems scientists, physicians, and biotechnology industry to the concept, practice, and value of responsible innovation, while glycomedicine and other emerging biomarker technologies (e.g., metagenomics and pharmacomicrobiomics) transition to applications in health care, ecology, pharmaceutical/diagnostic industries, agriculture, food, and bioengineering, among others.

Thromboelastography with Platelet Studies (TEG® with PlateletMapping®) After Rattlesnake Envenomation in the Southwestern United States Demonstrates Inhibition of ADP-Induced Platelet Activation As Well As Clot Lysis.

INTRODUCTION: Hematologic effects of North American rattlesnake envenomation can include fibrinogenolysis and thrombocytopenia, depending on species, geography, and other variables. During treatment, these effects are routinely monitored through assessment of fibrinogen concentrations and platelet counts. However, these tests provide no information about fibrinolysis or platelet dysfunction, both of which can also occur with venom from some species. METHODS: This was a retrospective chart review of patients admitted to a quaternary care academic hospital (Banner - University Medical Center Phoenix) in the southwestern United States for treatment of rattlesnake envenomation, over an approximately 1-year period from March 2017 through April 2018. Patients who had thromboelastography with platelet studies (TEG® with PlateletMapping®) during their care were included. RESULTS: Twelve patients were identified for this study. Four patients exhibited inhibition of ADP-induced platelet activation: one had normal fibrinogen and platelet count, two had concurrent hypofibrinogenemia, and one had concurrent thrombocytopenia. Crotalidae polyvalent immune Fab (ovine) reversed platelet inhibition in the single patient for whom serial thromboelastographs were available. Fibrinolysis was present in seven patients and resolved in the two patients with serial thromboelastographs. CONCLUSIONS: Inhibition of ADP-induced platelet aggregation and fibrinolysis occurred independent of hypofibrinogenemia and thrombocytopenia, indicating fibrinogen concentration (or protime) and platelet count monitoring alone is insufficient to assess the extent of hematologic toxicity in rattlesnake envenomation. Crotalidae polyvalent immune Fab (ovine) reversed platelet inhibition in one case, suggesting platelet inhibition could also be used in treatment decisions. Fibrinolysis could also be reversed, although the timing to antivenom administration was less clear.

The Effect of 4-Methylpyrazole on Oxidative Metabolism of Acetaminophen in Human Volunteers.

INTRODUCTION: Acetaminophen (APAP) is commonly ingested in both accidental and suicidal overdose. Oxidative metabolism by cytochrome P450 2E1 (CYP2E1) produces the hepatotoxic metabolite, N-acetyl-p-benzoquinone imine. CYP2E1 inhibition using 4-methylpyrazole (4-MP) has been shown to prevent APAP-induced liver injury in mice and human hepatocytes. This study was conducted to assess the effect of 4-MP on APAP metabolism in humans. METHODS: This crossover trial examined the ability of 4-MP to inhibit CYP2E1 metabolism of APAP in five human volunteers. Participants received a single oral dose of APAP 80 mg/kg, both with and without intravenous 4-MP, after which urinary and plasma oxidative APAP metabolites were measured. The primary outcome was the fraction of ingested APAP excreted as total oxidative metabolites (APAP-CYS, APAP-NAC, APAP-GSH). RESULTS: Compared with APAP alone, co-treatment with 4-MP decreased the percentage of ingested APAP recovered as oxidative metabolites in 24-hour urine from 4.48 to 0.51% (95% CI = 2.31-5.63%, p = 0.003). Plasma concentrations of these oxidative metabolites also decreased. CONCLUSIONS: These results show 4-MP effectively reduced oxidative metabolism of APAP in human volunteers ingesting a supratherapeutic APAP dose. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03878693.

Evaluation and treatment of acetaminophen toxicity.

A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12g or more acetaminophen (APAP) before risk of serious hepatotoxicity is of concern. A nomogram of serum APAP concentration vs hours post-ingestion can assist in determining risk of liver injury and need for treatment. However, histories concerning the time of ingestion and the amount of drug ingested are usually unreliable. Peak serum transaminase activities usually occur 48-96h after acute ingestion. It is possible for patients to present in liver failure days after ingestion with undetectable serum APAP concentrations. Patients who have chronically ingested excessive APAP doses and develop hepatotoxicity usually present with such, and renal failure is more common in this population. Current treatment centers on administration of N-acetylcysteine (NAC) to prevent hepatotoxicity, though NAC also improves outcomes in patients who present with acute liver failure. When given early after APAP ingestion, NAC's main mechanism of action is to maintain intracellular glutathione stores so to detoxify the electrophilic APAP metabolite, NAPQI. NAC is generally well-tolerated when given intravenously, with the main concern being anaphylactoid reactions. These reactions usually occur during loading doses and are easily treated with discontinuation of the NAC infusion, administration of antihistamines, and then restarting the loading dose at a slower infusion rate. There is concern that current NAC dosing is not large enough to adequately treat large APAP ingestions. Patients with acute liver failure may be candidates for orthotopic liver transplantation.

Responsible healthcare innovation: anticipatory governance of nanodiagnostics for theranostics medicine.

Theranostics signals the integrated application of molecular diagnostics, therapeutic treatment and patient response monitoring. Such integration has hitherto neglected another crucial dimension: coproduction of theranostic scientific knowledge, novel technological development and broader sociopolitical systems whose boundaries are highly porous. Nanodiagnostics applications to theranostics are one of the most contested and potentially volatile postgenomics innovation trajectories as they build on past and current tensions and promises surrounding both nanotechnology and personalized medicine. Recent science policy research suggests that beneficial outcomes of innovations do not simply flow from the generation of scientific knowledge and technological capability in a linear or automatic fashion. Thus, attempts to offset public concerns about controversial emerging technologies by expert risk assurances can be unproductive. Anticipation provides a more robust basis for governance that supports genuine healthcare progress. This article presents a synthesis of novel policy approaches that directly inform theranostics medicine and the future(s) of postgenomics healthcare.

Testosterone replacement and prostate cancer.

This article is intended as a review of the available clinical data outlining the risks and benefits of testosterone (androgen) replacement therapy, specifically addressing the issue of the relationship between exogenous androgen administration and prostate cancer risk. There is controversy over whether androgen replacement is a risk factor for incident prostate cancer. Our review of current clinical information revealed that to date, no study or review has definitively shown that androgen replacement therapy is an independent risk factor for development of prostate cancer. Androgen administration seems to be beneficial in decreasing fatal cardiovascular events, body fat mass, and insulin resistance. Overall, the current clinical data seems to suggest that androgen replacement is an appropriate therapeutic option for men with symptomatic hypogonadism provided that patients continue to receive regular prostate screenings.

Full field optical coherence tomography can identify spermatogenesis in a rodent sertoli-cell only model.

BACKGROUND: Microdissection testicular sperm extraction (micro-TESE) has replaced conventional testis biopsies as a method of choice for obtaining sperm for in vitro fertilization for men with nonobstructive azoospermia. A technical challenge of micro-TESE is that the low magnification inspection of the tubules with a surgical microscope is insufficient to definitively identify sperm-containing tubules, necessitating tissue removal and cytologic assessment. Full field optical coherence tomography (FFOCT) uses white light interference microscopy to generate quick high-resolution tomographic images of fresh (unprocessed and unstained) tissue. Furthermore, by using a nonlaser safe light source (150 W halogen lamp) for tissue illumination, it ensures that the sperm extracted for in vitro fertilization are not photo-damaged or mutagenized. MATERIALS AND METHODS: A focal Sertoli-cell only rodent model was created with busulfan injection in adult rats. Ex vivo testicular tissues from both normal and busulfan-treated rats were imaged with a commercial modified FFOCT system, Light-CT™, and the images were correlated with gold standard hematoxylin and eosin staining. RESULTS: Light-CT™ identified spermatogenesis within the seminiferous tubules in freshly excised testicular tissue, without the use of exogenous contrast or fixation. Normal adult rats exhibited tubules with uniform size and shape (diameter 328 ±11 µm). The busulfan-treated animals showed marked heterogeneity in tubular size and shape (diameter 178 ± 35 µm) and only 10% contained sperm within the lumen. CONCLUSION: FFOCT has the potential to facilitate real-time visualization of spermatogenesis in humans, and aid in micro-TESE for men with infertility.

Editorial overview: public science and technology scholars: engaging whom?

Science policy mandates across the industrialized world insinuate more active roles for publics, their earlier participation in policy decisions, and expanded notions of science and technology governance. In response to these policies, engaged scholars in science studies have sought to design and conduct exercises aimed at better attuning science to its public contexts. As demand increases for innovative and potentially democratic forms of public engagement with science and technology, so also do the prospects for insights from science studies to contribute to policy agendas and institutional capabilities. This collection brings together an international set of scholars in science, technology and society who inquire into the meaning, efficacy and responsibility of engaged science studies scholarship as a public matter.

Identification of spermatogenesis with multiphoton microscopy: an evaluation in a rodent model.

PURPOSE: Microdissection testicular sperm extraction has replaced conventional testis biopsies for men with nonobstructive azoospermia and it has become first line treatment. The current problem is that the decision to retrieve tubules is based only on appearance and there is no guarantee that the tubules removed contain sperm. Multiphoton microscopy enables label-free immediate visualization of many biological processes in living tissue at subcellular resolution. MATERIALS AND METHODS: We used multiphoton microscopy to study the different developmental stages of spermatogenesis using neonatal, pubertal and adult rat testes. We used a testis hypothermia plus ischemia model to study different testicular histopathologies with multiphoton microscopy. To assess the risk of photo damage DNA fragmentation in testis biopsies imaged at different intensities was assessed by TUNEL assay. RESULTS: Multiphoton microscopy identified the stage of spermatogenesis in a seminiferous tubule in fresh tissue without using exogenous labels. We noted significant differences in fluorescence and spectroscopic characteristics between tubules with and without sperm. Sertoli's-cell only tubules had abundant autofluorescence in the 420 to 490 and 550 to 650 nm wavelength ranges while tubules containing sperm had autofluorescence only in the 420 to 490 nm range. On DNA fragmentation assay sperm from tubules imaged by multiphoton microscopy had minimal DNA fragmentation at the laser intensities needed to distinguish tubules with and without sperm. CONCLUSIONS: Multiphoton microscopy has the potential to facilitate real-time visualization of spermatogenesis in humans and aid in clinical applications, such as testicular sperm extraction for men with infertility.

Legislating the laboratory? Promotion and precaution in a nanomaterials company.

Legislation is a form of governance that directs attention and prescribes action. Within the domain of nanoscience, the US 21st Century Nanotechnology Research and Development Act contains mandates not only for rapid development for economic competitiveness but also for responsible implementation, which is required to take place by integrating societal considerations into research and development. This chapter investigates whether these two mandates tend more to coexist or compete with one another, both in the purview of nanoscience policy and in the venue of nanoscience practice. This chapter first reviews macrolevel analysis of the directives contained in the legislation. It then examines, drawing on an empirical case study, how these directives manifest at the microlevel of a nanoscience research and development laboratory.

Duration of microdissection testicular sperm extraction procedures: relationship to sperm retrieval success.

PURPOSE: We evaluated the operative time of microdissection testicular sperm extraction in successful and failed procedures to identify the chance of sperm retrieval during longer microsurgical procedures. MATERIALS AND METHODS: A total of 793 men with nonobstructive azoospermia underwent a first attempt at microdissection testicular sperm extraction from January 2000 to September 2009. Clinical factors were analyzed, including age, testicular volume, endocrinological data and histology. Operative time was calculated from incision until the procedure was terminated. RESULTS: Testicular sperm were successfully retrieved in 57% of the men. Sperm were found within 2, 2 to 4 and 4 to 7 hours in 89%, 30% and 37% of the men, respectively. There were no differences in preoperative clinical characteristics, age, follicle-stimulating hormone, testicular volume, incidence of a Klinefelter's syndrome diagnosis and distribution of most advanced histopathology in patients in the 3 operative time groups. In men in whom sperm were retrieved the clinical pregnancy and live birth rates were 48%, 45% and 29%, and 37%, 30% and 29% for operative times up to 2, 2 to 4 and 4 to 7 hours, respectively (p >0.05). ROC curve analysis of the different operative times for detecting sperm showed that 125 minutes was the most accurate time (AUC 0.81) with 84% sensitivity and 95% specificity. CONCLUSIONS: The chance of sperm retrieval during microdissection testicular sperm extraction was best during the first 2 hours of the operation. However, sperm were still found in up to 37% of men who required greater than 4 hours of microdissection. Retrospective analysis of our data indicated no cutoff point after which sperm retrieval was uniformly unsuccessful.