The Surgical Management of Acromegaly

Acromegaly is the condition produced by one of the benign tumors of the pituitary gland. These tumors produce a variety of disorders affecting many parts of the body, producing side effects related to abnormal hormone function. The dramatic appearance of the acromegalic giant has attracted attention over the ages. This chapter summarizes the history of the recognition and ultimate diagnosis of acromegaly. The biological and physiological elements are described. The methods of diagnosis and management are elaborated. Although the focus of the chapter is on the surgical approach for treatment, alternative strategies are also discussed, along with the outcomes of management for patients and the restoration of quality of life as a primary goal

Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

PURPOSE: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. METHODS: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. RESULTS: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. CONCLUSIONS: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management

Discovery of a missense mutation (Q222K) of the APOE gene from the Australian imaging, biomarker and lifestyle study

After age, polymorphisms of the Apolipoprotein E (APOE) gene are the biggest risk factor for the development of Alzheimer\u27s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ϵ2, ϵ3, and ϵ4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ϵ4 (Q222K) mutation did not form dimers or complexes observed for apoE ϵ2 ϵ3 proteins

Pelagic Functional Group Modeling: Progress, Challenges and Prospects

In this paper, we review the state of the art and major challenges in current efforts to incorporate biogeochemical functional groups into models that can be applied on basin-wide and global scales, with an emphasis on models that might ultimately be used to predict how biogeochernical cycles in the ocean will respond to global warming. We define the term biogeochemical functional group to refer to groups of organisms that mediate specific chemical reactions in the ocean. Thus, according to this definition, functional groups have no phylogenetic meaning-these are composed of many different species with common biogeochemical functions. Substantial progress has been made in the last decade toward quantifying the rates of these various functions and understanding the factors that control them. For some of these groups, we have developed fairly sophisticated models that incorporate this understanding, e.g. for diazotrophs (e.g. Trichodesmium), silica producers (diatoms) and calcifiers (e.g. coccolithophorids and specifically Emiliania huxleyi). However, current representations of nitrogen fixation and calcification are incomplete, i.e., based primarily upon models of Trichodesmium and E huxleyi, respectively, and many important functional groups have not yet been considered in open-ocean biogeochemical models. Progress has been made over the last decade in efforts to simulate dimethylsulfide (DMS) production and cycling (i.e., by dinoflagellates and prymnesiophytes) and denitrification, but these efforts are still in their infancy, and many significant problems remain. One obvious gap is that virtually all functional group modeling efforts have focused on autotrophic microbes, while higher trophic levels have been completely ignored. It appears that in some cases (e.g., calcification), incorporating higher trophic levels may be essential not only for representing a particular biogeochemical reaction, but also for modeling export. Another serious problem is our tendency to model the organisms for which we have the most validation data (e.g., E huxleyi and Trichodesmium) even when they may represent only a fraction of the biogeochemical functional group we are trying to represent. When we step back and look at the paleo-oceanographic record, it suggests that oxygen concentrations have played a central role in the evolution and emergence of many of the key functional groups that influence biogeochemical cycles in the present-day ocean. However, more subtle effects are likely to be important over the next century like changes in silicate supply or turbulence that can influence the relative success of diatoms versus dinoflagellates, coccolithophorids and diazotrophs. In general, inferences drawn from the paleo-oceanographic record and theoretical work suggest that global warming will tend to favor the latter because it will give rise to increased stratification. However, decreases in pH and Fe supply could adversely impact coccolithophorids and diazotrophs in the future. It may be necessary to include explicit dynamic representations of nitrogen fixation, denitrification, silicification and calcification in our models if our goal is predicting the oceanic carbon cycle in the future, because these processes appear to play a very significant role in the carbon cycle of the present-day ocean and they are sensitive to climate change. Observations and models suggest that it may also be necessary to include the DMS cycle to predict future climate, though the effects are still highly uncertain. We have learned a tremendous amount about the distributions and biogeochemical impact of bacteria in the ocean in recent years, yet this improved understanding has not yet been incorporated into many of our models. All of these considerations lead us toward the development of increasingly complex models. However, recent quantitative model intercomparison studies suggest that continuing to add complexity and more functional groups to our ecosystem models may lead to decreases in predictive ability if the models are not properly constrained with available data. We also caution that capturing the present-day variability tells us little about how well a particular model can predict the future. If our goal is to develop models that can be used to predict how the oceans will respond to global warming, then we need to make more rigorous assessments of predictive skill using the available data

A new method for estimating growth rates of alkenone-producing haptophytes

Laboratory culture experiments were performed to establish the range of growth conditions where ¹³C labeling of di- and tri-unsaturated C₃₇ methyl ketones yields reliable growth rates for alkenone-producing algae. Results document that even at low growth rates and short time intervals, ¹³C labeling of the di-unsaturated C₃₇ alkenone provides reasonable estimates of growth rate for Isochrysis galbana, Isochrysis sp., and three strains of Emiliania huxleyi. These findings suggest that although alkenone biosynthesis almost certainly involves a complex combination of intermediate pools, those pools must turn over at a rate sufficiently fast that the labeling of the di-unsaturated C₃₇ alkenone is not greatly biased. However, bias was noted for the tri-unsaturated alkenone, suggesting that either growth rates in the field should be based on K₃₇:₂ labeling or that long incubations should be used. Specific growth rates calculated from alkenone ¹³C labeling experiments conducted in the subarctic Pacific decreased as a function of depth in the euphotic zone and were linearly correlated with photosynthetically active radiation below ∼50 µEin m⁻² s⁻¹. These observations indicate that at depths greater than ∼25 m, growth rates of the alkenone-producing algae were light-limited. Determination of the specific growth rates of the alkenone-producing algae was motivated by our present knowledge of the controls on stable carbon isotopic fractionation in marine microalgae. Development of our alkenone ¹³C labeling technique for in situ growth rate determinations allows evaluation of the effect of growth rate on carbon isotopic fractionation in natural populations of E. huxleyi and Gephyrocapsa oceanica so that laboratory-based microalgal stable isotope fractionation hypotheses may be evaluated in the field

Ecology of \u3ci\u3eVibrio parahaemolyticus\u3c/i\u3e and \u3ci\u3eVibrio vulnificus\u3c/i\u3e in the Coastal and Estuarine Waters of Louisiana, Maryland, Mississippi, and Washington (United States)

Vibrio parahaemolyticus and Vibrio vulnificus, which are native to estuaries globally, are agents of seafood-borne or wound infections, both potentially fatal. Like all vibrios autochthonous to coastal regions, their abundance varies with changes in environmental parameters. Sea surface temperature (SST), sea surface height (SSH), and chlorophyll have been shown to be predictors of zooplankton and thus factors linked to vibrio populations. The contribution of salinity, conductivity, turbidity, and dissolved organic carbon to the incidence and distribution of Vibrio spp. has also been reported. Here, a multicoastal, 21-month study was conducted to determine relationships between environmental parameters and V. parahaemolyticus and V. vulnificus populations in water, oysters, and sediment in three coastal areas of the United States. Because ecologically unique sites were included in the study, it was possible to analyze individual parameters over wide ranges. Molecular methods were used to detect genes for thermolabile hemolysin (tlh), thermostable direct hemolysin (tdh), and tdh-related hemolysin (trh) as indicators of V. parahaemolyticus and the hemolysin gene vvhA for V. vulnificus. SST and suspended particulate matter were found to be strong predictors of total and potentially pathogenic V. parahaetnolyticus and V. vulnificus. Other predictors included chlorophyll a, salinity, and dissolved organic carbon. For the ecologically unique sites included in the study, SST was confirmed as an effective predictor of annual variation in vibrio abundance, with other parameters explaining a portion of the variation not attributable to SST

Halobacteriovorax, an underestimated predator on bacteria: potential impact relative to viruses on bacterial mortality

Predation on bacteria and accompanying mortality are important mechanisms in controlling bacterial populations and recycling of nutrients through the microbial loop. The agents most investigated and seen as responsible for bacterial mortality are viruses and protists. However, a body of evidence suggests that predatory bacteria such as the Halobacteriovorax (formerly Bacteriovorax), a Bdellovibrio-like organism, contribute substantially to bacterial death. Until now, conclusive evidence has been lacking. The goal of this study was to better understand the contributors to bacterial mortality by addressing the poorly understood role of Halobacteriovorax and how their role compares with that of viruses. The results revealed that when a concentrated suspension of Vibrio parahaemolyticus was added into microcosms of estuarine waters, the native Halobacteriovorax were the predators that responded first and most rapidly. Their numbers increased by four orders of magnitude, whereas V. parahaemolyticus prey numbers decreased by three orders of magnitude. In contrast, the extant virus population showed little increase and produced little change in the prey density. An independent experiment with stable isotope probing confirmed that Halobacteriovorax were the predators primarily responsible for the mortality of the V. parahaemolyticus. The results show that Halobacteriovorax have the potential to be significant contributors to bacterial mortality, and in such cases, predation by Halobacteriovorax may be an important mechanism of nutrient recycling. These conclusions add another dimension to bacterial mortality and the recycling of nutrients

MAPK activation and HRAS mutation identified in pituitary spindle cell oncocytoma

Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection