"[This] system was not made for [you]:" A case for decolonial Scientia.

BACKGROUND: Sylvia Wynter's "recoded" form of science called decolonial Scientia (DS) is grounded in an understanding of humans as simultaneously biological and cultural. DS includes narrative interventions that destabilize Western scientific authority, and address limitations that empirical data collection and analysis place on capturing simultaneous realities. Therefore, Wynter's narrative "languaging" is both scientific critique and grounded in a tradition of Black radical imagining. AIMS: In this article, I use languaging to destabilize the canonical narrative tied to W. M. Cobb's production of the article "Race and Runners." The standard telling focuses on Cobb's examination of Owens' lower extremities to expose the fallacy of racial differences in athletic ability. Destabilization of the narrative allows for identifying relational complexities between actors involved in the canonical story - and identifying ideologies embedded within it that guide our deconstructions of biological race. My alter(ed)native subjectivity informs my use of languaging to argue that the relationship between narrative and research practices belie Western scientific/unscientific binaries. MATERIALS AND METHODS: Audiovisual and documentary sources of the public-facing "Race and Runners" story were subject to comparative analysis to verify the content and order of events in the canonical narrative. Letters focused on race and athletic ability obtained from the W. Montague Cobb Manuscript Collection at Howard University serve as "apocryphal" sources of information. Correspondence between Cobb and a representative member of the public named Howard Duncan took place within a period immediately before, during and after Cobb publishes "Race and Runners" in the Journal of Health and Physical Education. Contents were subject to a systematic analysis that involved reviewing documents to identify statements reflecting scientific practices, human interactions and relationships between race and athletic ability reflected in the canonical narrative. Contents were also examined for statements relevant to the narrative that departed from or added to the canonical story in the same three areas. Details regarding departures and additions were recorded along with the specific part of the narrative to which they corresponded. Narrative departures and additions were articulated with the canonical narrative in the interest of destabilizing it to identify "knots of ideas, histories and narratives that, contrary to Western science, can only be legible in relation to one another" (McKittrick, 2015b p. 2). RESULTS: Letters exchanged between Cobb and Duncan reveal dynamics that are obscured in the canonical storyline. For instance, Duncan's ability as a white male to assert himself as Cobb's peer demonstrates how racialized power is enacted through science. This is also reflected in Owens' position in the narrative as a voiceless object of knowledge. Letters also present Cobb's identity beyond being a "pioneer," rendering how he is studying and experiencing racism. This includes how he refuses to engage Duncan as a peer. DISCUSSION: More than mere stories, narratives are motivating and instructive forces that shape how we study human biology and use our research to oppose biological notions of race. Correspondence between Cobb and Duncan reveals how Western scientific ideologies that reinforce prescribed roles and boundaries are embedded in narratives. These ideologies can limit the transformative potential of our approaches to contesting biological notions of race.

Utility of venous blood gases for the assessment of traumatic shock: a prospective observational study.

BACKGROUND: ABG samples are often obtained in trauma patients to assess shock severity. Venous blood gas (VBG) sampling, which is less invasive, has been widely used to assess other forms of shock. The study aim was to determine the agreement between VBG and ABG measurements in trauma. METHODS: Patients were enrolled at an Australian trauma centre between October 2016 and October 2018. Bland-Altman limits of agreement (LOA) between paired blood gas samples taken <30 min apart were used to quantify the extent of agreement. The impact of using only VBG measurements was considered using an a priori plan. Cases where venous sampling failed to detect 'concerning levels' were flagged using evidence-based cut-offs: pH ≤7.2, base deficit (BD) ≤-6, bicarbonate <21 and lactate ≥4. Case summaries of these patients were assessed by independent trauma clinicians as to whether an ABG would change expected management. RESULTS: During the study period 176 major trauma patients had valid paired blood gas samples available for analysis. The median time difference between paired measurements was 11 min (IQR 6-17). There was a predominance of men (81.8%) and blunt trauma (92.0%). Median Injury Severity Score was 13 (range 1-75) and inpatient mortality was 6.3%. Mean difference (ABG-VBG) and LOA between paired arterial and venous measurements were 0.036 (LOA -0.048 to 0.120) for pH, -1.27 mmol/L (LOA -4.35 to 1.81) for BD, -0.64 mmol/L (LOA -1.86 to 0.57) for lactate and -1.97 mmol/L (LOA -5.49 to 1.55) for bicarbonate. Independent assessment of the VBG 'false negative' cases (n=20) suggested an ABG would change circulatory management in two cases. CONCLUSIONS: In trauma patients VBG and ABG parameters displayed suboptimal agreement. However, in cases flagged as VBG 'false negative' independent review indicated that the availability of an ABG was unlikely to change management.

The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.

The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus.

Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder of eye movement that can be caused by mutations in the FRMD7 gene that encodes a FERM domain protein. FRMD7 is expressed in the brain and knock-down studies suggest it plays a role in neurite extension through modulation of the actin cytoskeleton, yet little is known about its precise molecular function and the effects of IIN mutations. Here, we studied four IIN-associated missense mutants and found them to have diverse effects on FRMD7 expression and cytoplasmic localization. The C271Y mutant accumulates in the nucleus, possibly due to disruption of a nuclear export sequence located downstream of the FERM-adjacent domain. While overexpression of wild-type FRMD7 promotes neurite outgrowth, mutants reduce this effect to differing degrees and the nuclear localizing C271Y mutant acts in a dominant-negative manner to inhibit neurite formation. To gain insight into FRMD7 molecular function, we used an IP-MS approach and identified the multi-domain plasma membrane scaffolding protein, CASK, as a FRMD7 interactor. Importantly, CASK promotes FRMD7 co-localization at the plasma membrane, where it enhances CASK-induced neurite length, whereas IIN-associated FRMD7 mutations impair all of these features. Mutations in CASK cause X-linked mental retardation. Patients with C-terminal CASK mutations also present with nystagmus and, strikingly, we show that these mutations specifically disrupt interaction with FRMD7. Together, our data strongly support a model whereby CASK recruits FRMD7 to the plasma membrane to promote neurite outgrowth during development of the oculomotor neural network and that defects in this interaction result in nystagmus.

A novel mechanism of sodium iodide symporter repression in differentiated thyroid cancer.

Differentiated thyroid cancers and their metastases frequently exhibit reduced iodide uptake, impacting on the efficacy of radioiodine ablation therapy. PTTG binding factor (PBF) is a proto-oncogene implicated in the pathogenesis of thyroid cancer. We recently reported that PBF inhibits iodide uptake, and have now elucidated a mechanism by which PBF directly modulates sodium iodide symporter (NIS) activity in vitro. In subcellular localisation studies, PBF overexpression resulted in the redistribution of NIS from the plasma membrane into intracellular vesicles, where it colocalised with the tetraspanin CD63. Cell-surface biotinylation assays confirmed a reduction in plasma membrane NIS expression following PBF transfection compared with vector-only treatment. Coimmunoprecipitation and GST-pull-down experiments demonstrated a direct interaction between NIS and PBF, the functional consequence of which was assessed using iodide-uptake studies in rat thyroid FRTL-5 cells. PBF repressed iodide uptake, whereas three deletion mutants, which did not localise within intracellular vesicles, lost the ability to inhibit NIS activity. In summary, we present an entirely novel mechanism by which the proto-oncogene PBF binds NIS and alters its subcellular localisation, thereby regulating its ability to uptake iodide. Given that PBF is overexpressed in thyroid cancer, these findings have profound implications for thyroid cancer ablation using radioiodine.

The Road to Survival for Haemodynamically Unstable Patients With Open Pelvic Fractures.

Management of haemodynamically unstable pelvic ring injuries has been simplified into treatment algorithms to streamline care and emergent decision making in order to improve patient outcomes whilst decreasing mortality and morbidity. Pelvic ring injuries are most commonly a result of high-velocity and energy forces that exert trauma to the pelvic bones causing not only damage to the bone but the surrounding soft-tissue, organs, and other structures and are usually accompanied by injuries to other parts of the body resulting in a polytraumatised patient. Open pelvic fractures are a rare subset of pelvic ring fractures that are on the more severe end of the pelvic fracture continuum and usually produce uncontrolled haemorrhage from fractured bone, retroperitoneal haematomas, intraabdominal bleeding from bowel injury, soft tissue injuries to the anus, perineum, and genitals, fractures of the pelvic bones, causing bleeding from cancellous bone, venous, and arterial injuries combined with bleeding from concomitant injuries. This is a very complex and challenging clinical situation and timely and appropriate decisions and action are paramount for a positive outcome. Consequently, open pelvic fractures have an extremely high rate of mortality and morbidity and outcomes remain poor, despite evidence-based improvements in treatment, knowledge, and identification of haemorrhage; in the pre-hospital, critical care, and operative settings. In the future utilisation of haemostatic drugs, dressings, devices, and procedures may aid in the time to haemorrhage control.

Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin.

CONTEXT: Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates. OBJECTIVE: The proto-oncogene PTTG1-binding factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumor aggressiveness. This study aimed to understand the role of PBF in tumor cell invasion and identify possible routes to inhibit its action. Design, Setting, Patients, and Interventions: Thyroid, breast, and colorectal cells were transfected with PBF and cultured for in vitro analysis. PBF and cortactin (CTTN) expression was determined in differentiated thyroid cancer and The Cancer Genome Atlas RNA-seq data. PRIMARY OUTCOME MEASURE: Pro-invasive effects of PBF were evaluated by 2D Boyden chamber, 3D organotypic, and proximity ligation assays. RESULTS: Our study identified that PBF and CTTN physically interact and co-localize, and that this occurs at the cell periphery, particularly at the leading edge of migrating cancer cells. Critically, PBF induces potent cellular invasion and migration in thyroid and breast cancer cells, which is entirely abrogated in the absence of CTTN. Importantly, we found that CTTN is over-expressed in differentiated thyroid cancer, particularly in patients with regional lymph node metastasis, which significantly correlates with elevated PBF expression. Mutation of PBF (Y174A) or pharmacological intervention modulates the PBF: CTTN interaction and attenuates the invasive properties of cancer cells. CONCLUSION: Our results demonstrate a unique role for PBF in regulating CTTN function to promote endocrine cell invasion and migration, as well as identify a new targetable interaction to block tumor cell movement.

The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.

The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a protooncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity-ligation assays, we show that PBF binds specifically to p53 in thyroid cells and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF overexpression (transgenic PBF mice), which had significantly increased genetic instability as indicated by fluorescent inter simple sequence repeat-PCR analysis. Consistent with this, approximately 40% of all DNA repair genes examined were repressed in transgenic PBF primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51, and Xrcc3. Our data also revealed that PBF induction resulted in up-regulation of the E2 enzyme Rad6 in murine thyrocytes and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the protooncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, in which PBF is generally overexpressed and p53 mutations are rare compared with other tumor types.

The Role of FRMD7 in Idiopathic Infantile Nystagmus.

Idiopathic infantile nystagmus (IIN) is an inherited disorder in which the nystagmus arises independently of any other symptoms, leading to the speculation that the disorder represents a primary defect in the area of the brain responsible for ocular motor control. The inheritance patterns are heterogeneous, however the most common form is X-linked. FRMD7 resides at Xq26-27 and approximately 50% of X-linked IIN families map to this region. Currently 45 mutations within FRMD7 have been associated with IIN, confirming the importance of FRMD7 in the pathogenesis of the disease. Although mutations in FRMD7 are known to cause IIN, very little is known about the function of the protein. FRMD7 contains a conserved N-terminal FERM domain suggesting that it may provide a link between the plasma membrane and actin cytoskeleton. Limited studies together with the knowledge of the function of other FERM domain containing proteins, suggest that FRMD7 may play a role in membrane extension during neuronal development through remodeling of the actin cytoskeleton.

Pituitary tumor transforming gene binding factor: a new gene in breast cancer.

Pituitary tumor transforming gene (PTTG) binding factor (PBF; PTTG1IP) is a relatively uncharacterized oncoprotein whose function remains obscure. Because of the presence of putative estrogen response elements (ERE) in its promoter, we assessed PBF regulation by estrogen. PBF mRNA and protein expression were induced by both diethylstilbestrol and 17beta-estradiol in estrogen receptor alpha (ERalpha)-positive MCF-7 cells. Detailed analysis of the PBF promoter showed that the region -399 to -291 relative to the translational start site contains variable repeats of an 18-bp sequence housing a putative ERE half-site (gcccctcGGTCAcgcctc). Sequencing the PBF promoter from 122 normal subjects revealed that subjects may be homozygous or heterozygous for between 1 and 6 repeats of the ERE. Chromatin immunoprecipitation and oligonucleotide pull-down assays revealed ERalpha binding to the PBF promoter. PBF expression was low or absent in normal breast tissue but was highly expressed in breast cancers. Subjects with greater numbers of ERE repeats showed higher PBF mRNA expression, and PBF protein expression positively correlated with ERalpha status. Cell invasion assays revealed that PBF induces invasion through Matrigel, an action that could be abrogated both by siRNA treatment and specific mutation. Furthermore, PBF is a secreted protein, and loss of secretion prevents PBF inducing cell invasion. Given that PBF is a potent transforming gene, we propose that estrogen treatment in postmenopausal women may upregulate PBF expression, leading to PBF secretion and increased cell invasion. Furthermore, the number of ERE half-sites in the PBF promoter may significantly alter the response to estrogen treatment in individual subjects.