An Analysis of Otolaryngology's NIH Research Funding Compared to Other Specialties.

OBJECTIVE: To compare NIH funding in the field of Otolaryngology to other medical and surgical specialties between 2009 and 2019. METHODS: Data was collected from the NIH RePORTER database on funding dollars received by each specialty from 2009 to 2019. Along with data on total active physicians per specialty using the Physician Specialty Data Book, comparisons were drawn between Otolaryngology and other medical and surgical specialties with regards to trends in total funding and NIH funding dollars per physician. The distributions of grant funding, within Otolaryngology from various NIH institutes among principal investigators, organizations, and subspecialties were further explored. RESULTS: There were 3810 grants (1147 unique projects) for a total of $1 276 198 555 funded by the NIH to Otolaryngology departments from 2009 to 2019. Statistically insignificant funding increases (P > .05) caused otolaryngology to fall from first to fourth in funding among studied specialties. The National Institute on Deafness and Other Communication Disorders funded 57% of all unique projects, and 57.2% of all unique NIH projects were otology related. Most projects were basic science related. The top 10 principal investigators obtained 22.3% of the total NIH funding for Otolaryngology. The top 3 organizations over the studied period comprised 26.55% of the total funding, generating a combined 729 grants. Among principal investigators, 63.0% had a PhD degree, 25.3% had an MD, and 9.6% had an MD/PhD. CONCLUSION AND RELEVANCE: NIH funding in Otolaryngology has remained stable and is highly concentrated among a small number of organizations, geographic regions, and principal investigators. Recent initiatives by academic communities have sought to address funding disparities by incorporating diversity and inclusion into clinician-scientist pipelines. We urge our colleagues to strive toward identification of the factors that contribute to successful acquisition of funding and implementation of a more conducive institutional infrastructure to produce research.

Conformational change of the Bordetella response regulator BvgA accompanies its activation of the B. pertussis virulence gene fhaB.

The BvgAS two-component system regulates virulence gene expression in Bordetella pertussis. Although precise three-dimensional structural information is not available for the response regulator BvgA, its sequence conservation with E. coli NarL and previous studies have indicated that it is composed of 3 domains: an N-terminal domain (NTD) containing the phosphorylation site, a linker, and a DNA-binding C-terminal domain (CTD). Previous work has determined how BvgACTD dimers interact with the promoter (P fhaB ) of fhaB, the gene encoding the virulence adhesin filamentous hemagglutinin. Here we use molecular modeling, FeBABE footprinting, and crosslinking to show that within the transcription complex of phosphorylated BvgA (BvgA âˆ¼ P), B. pertussis RNAP, and P fhaB , the NTDs displace from the CTDs and are positioned at specific locations relative to the three BvgA âˆ¼ P binding sites. Our work identifies a patch of the NTD that faces the DNA and suggests that BvgA âˆ¼ P undergoes a conformational rearrangement that relocates the NTD to allow productive interaction of the CTD with the DNA.

Nature and significance of stromal differentiation in carcinosarcoma (MMMT): unravelling the biology and shifting current paradigms.

Carcinosarcoma (CS) is a rare, aggressive malignancy of the Mullerian system often termed mixed malignant Mullerian tumor (MMMT). It is biphasic in nature, differentiating into epithelial and sarcomatous components. Tumor-node-metastasis (TNM) staging and mismatch repair (MMR) status is the basis for both prognostication and therapeutic decision making. However, stromal differentiation (SD) is a new frontier in the field of histopathology and many studies have demonstrated its prognostic significance. The present study is the first study to evaluate the role of SD in carcinosarcoma. Here we found immature SD to be a significant prognostic signature (p = 0.04). It outperformed age, nodal metastasis, and lymphovascular invasion for predicting cancer-free survival. Immature SD also corelated with both myometrial invasion (p = 0.01) and tumor stage (p = 0.02). Carcinosarcoma has been previously thought to have universally poor outcomes; however, mature SD was found to be protective in this cancer subtype. Our findings support the integration of SD into the synoptic reporting for carcinosarcoma; however, this will require pathologists to shoulder the adoption of SD into clinical practice.

A Holistic Appraisal of Stromal Differentiation in Colorectal Cancer: Biology, Histopathology, Computation, and Genomics.

Cancer comprises epithelial tumor cells and associated stroma, often times referred to as the "tumoral microenvironment". Cancer-associated fibroblasts (CAFs) are the most notable components of the tumor mesenchyme. CAFs promote the initiation of cancer through angiogenesis, invasion and metastasis. Histologically, the differentiation of stroma has been reported to correlate with prognostic outcomes in patients with colorectal cancer. This review summarizes our current understanding of the extracellular matrix (ECM) in colorectal carcinoma (CRC), showcasing the functions of CAFs and its role in stromal differentiation (SD). We also review current state-of-the-art biology, histopathology, computation, and genomics in the setting of the stroma. SD is distinctive morphologically, and is easily recognized by a surgical pathologist; we offer a lexicon and guide for discovering the essence of stroma, as well as an incipient vision of the future for computation and molecular genomics. We propose that the mesenchymal phenotype, which encompasses a cancer migratory/metastatic capacity, could occur through the process of SD. Looking forward, pathologists will need to invest time and energy into SD, embracing the concept and propagating its use. For patients with colorectal cancer, stroma is a brave new frontier, one not only rich in biologic diversity, but also potentially critical for therapeutic decision making.

Whole slide imaging and colorectal carcinoma: A validation study for tumor budding and stromal differentiation.

Whole slide imaging (WSI) has recently received FDA approval for sign out in surgical pathology and some anticipate this to mature into the gold standard. During this transition, it will be important to validate WSI for its intended use. And many studies have validated whole slide imaging by comparing diagnostic accuracy with that of conventual light microscopy (CLM); however, the assessment of histopathologic markers is prone to much more discrepancy. One of the best examples being tumor-bud scoring in colorectal carcinoma. Other signatures, including stromal differentiation or desmoplastic reaction; could better represent the epithelial-mesenchymal transition. The findings in our study suggest stromal differentiation on both digital and glass slides to be much more reproducible (0.3585-0.9368) when compared to tumor budding (0.0968-0.7871). When comparing interobserver variation between glass and digital slides for three observers; stromal differentiation was more reliable on glass slides (0.4492), when compared to its digital counterpart (0.3016). On the other hand, interobserver variation for tumor bud scoring was more reliable on digital (0.1661), than glass slides (0.1026). Overall, there is significant variation between different observers and reproducibility issues present on conventual light microscopy transfer to digital slides. Although it is possible that too much emphasis is being placed on the concordance of WSI with CLM. In future, applications in artificial intelligence may be key to diagnostic precision and improved patient outcomes.