New Faculty Achievements
A number of UT Southwestern Pathology faculty have released new publications, and have accomplished incredible achievements! Please join us in congratulating them for their accomplishments!
Dr. Ruby Chang Wins a Stowell-Orbinson Certificate of Merit
Dr. Ruby Chang has won a Stowell-Orbinson Certificate of Merit. Her achievement was recognized Thursday, March 18, during the USCAP Honors Session. Please join us in congratulating Dr. Chang!
PATH Faculty involved: Yang-Xin Fu, M.D., Ph.D.
Journal: Clinical Cancer Research
Immune checkpoint inhibitors (ICI) are successful immunotherapy modalities that enhance CD8+ T cell responses. Although T cells are initially primed in draining lymph nodes (LNs), the mechanisms that underlie their reactivation inside the tumor microenvironment (TME) are less clear. Recent studies have found that not only is the cross-priming of conventional type 1 dendritic cells (cDC1) required to initiate CD8+ T cell responses during tumor progression, but it also plays a central role in immunotherapy-mediated reactivation of tumor-specific CD8+ T cells for tumor regression. Moreover, many cancer treatment modalities trigger type I interferon (IFN) responses, which play critical roles in boosting cDC1 cross-priming and CD8+ T cell reactivation. Inducing type I IFNs within tumors can overcome innate immune resistance and activate anti-tumor adaptive immunity. Here, we review recent studies on how type I IFN-cDC1 cross-priming reactivates CD8+ T cells and contributes to tumor control by cancer immunotherapy.
PATH Faculty involved: Laura Filkins, Ph.D., and Jason Park, M.D., Ph.D.
A couple of our faculty were involved in the work of the linked Center Times article released March 8.
PATH Faculty involved: Dinesh Rakheja, M.D.; Charles Timmons, M.D., Ph.D.
Journal: International Journal of Surgical Pathology
We describe a previously unreported bronchopulmonary foregut malformation wherein a segment of a bronchus of the lower lobe of the left lung in a 4-year-old girl was entirely esophageal in structure. No communication was identified between the tracheobronchial tree and the esophagus by radiologic examination or at surgery. The esophagus-like bronchus was associated with an adjacent atretic bronchus and a downstream cavity in the lower lobe of the left lung. The child sought clinical attention because of recurrent pulmonary infections localized to the lower lobe of the lung. We posit that this esophagus-like bronchus is a novel noncommunicating bronchopulmonary foregut malformation.
PATH Faculty involved: Charles White, M.D.
Pathologists can have complementary assessments and focus areas when identifying and labeling neuropathologies. A standardized approach would ideally draw on the expertise of the entire cohort. We present a deep learning (DL) framework that consistently labels cored, diffuse, and cerebral amyloid angiopathy (CAA) neuropathologies using expert consensus. We collected 100,495 annotations, comprising 20,099 candidate neuropathologies from three institutions, independently annotated by five experts. We compared DL methods that learned the annotation behaviors of individual experts (AUPRC=0.67±0.06 cored; 0.48±0.06 CAA) versus those that reproduced expert consensus, yielding 8.9-13% improvements (AUPRC=0.73±0.03 cored; 0.54±0.06 CAA). Saliency mapping on neuropathologies illustrated how human expertise may progress from novice to expert. In blind prospective tests of 52,555 subsequently expert-annotated images, the models accurately labeled pathologies similar to their human counterparts (consensus model AUPRC=0.73 cored; 0.68 CAA).
Fine-tuning p53 activity by modulating the interaction between eukaryotic translation initiation factor eIF4E and RNA-binding protein RBM38
PATH Faculty involved: Mingyi Chen, M.D., Ph.D.
Journal: Genes & Development
p53 is critical for tumor suppression but also elicits detrimental effects when aberrantly overexpressed. Thus, multiple regulators, including RNA-binding protein RBM38, are found to tightly control p53 expression. Interestingly, RBM38 is unique in that it can either suppress or enhance p53 mRNA translation via altered interaction with eIF4E potentially mediated by serine-195 (S195) in RBM38. Thus, multiple RBM38/eIF4E knock-in (KI) cell lines were generated to investigate the significance of eIF4E-RBM38 interaction in controlling p53 activity. We showed that KI of RBM38-S195D or -Y192C enhances, whereas KI of RBM38-S195K/R/L weakens, the binding of eIF4E to p53 mRNA and subsequently p53 expression. We also showed that KI of eIF4E-D202K weakens the interaction of eIF4E with RBM38 and thereby enhances p53 expression, suggesting that D202 in eIF4E interacts with S195 in RBM38. Moreover, we generated an Rbm38 S193D KI mouse model in which human-equivalent serine-193 is substituted with aspartic acid. We showed that S193D KI enhances p53-dependent cellular senescence and that S193D KI mice have a shortened life span and are prone to spontaneous tumors, chronic inflammation, and liver steatosis. Together, we provide in vivo evidence that the RBM38-eIF4E loop can be explored to fine-tune p53 expression for therapeutic development.
Dr. Hasan Zaki Awarded His First NIH Grant
PATH Faculty involved: Hasan Zaki, Ph.D.
Grantor: National Institute of Diabetes and Digestive and Kidney Diseases
Human inflammatory bowel diseases (IBD), comprised of ulcerative colitis and Crohn’s disease, constitute a major health problem in developed countries. While precise etiology is not clearly defined, genetic predisposition, altered gut microbiota, and Western diet are risk factors for IBD. However, how dietary sugar contributes to IBD pathogenesis and how the immune system regulates sugar homeostasis in the gut are poorly understood. Dr. Zaki will be looking to determine the role of dietary glucose in colitis pathogenesis and to elucidate the role of the inflammasome in glucose homeostasis in the gut. The data obtained from this study will guide diet recommendations for IBD patients and lead to developing novel IBD treatments targeting the inflammasome or its downstream signaling pathways involved in glucose transport.
New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia
PATH Faculty involved: Rajal Shah, M.D., Payal Kapur, M.D.
Journal: Modern Pathology
The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with ‘borderline’ features between oncocytoma and chromophobe RCC, a term “oncocytic renal neoplasm of low malignant potential, not further classified” is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term “fumarate hydratase deficient RCC” (“FH-deficient RCC”) is preferred over “hereditary leiomyomatosis and RCC syndrome-associated RCC”. A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
Real-world application of pre-orchiectomy miR-371a-3p test in testicular germ cell tumor (GCT) management
PATH Faculty involved: Payal Kapur, M.D.; Liwei Jia, M.D., Ph.D.
Journal: Journal of Clinical Oncology
Background: Current serum tumor markers (STMs) for testicular germ cell tumor (GCT) are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) GCT management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable GCT among patients undergoing partial or radical orchiectomy.
Methods: Serum samples were collected from 69 consecutive patients pre-orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional STMs (AFP/β-hCG/LDH) between viable GCT patients and those without viable GCT on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. Kruskal-Wallis test and linear and ordinal regression models were used for analysis.
Results: For detecting viable GCT, combined conventional STMs had a specificity of 100%, sensitivity of 58%, and area under the curve (AUC) of 0.79 (Table). The miR-371a-3p test showed a specificity of 100%, sensitivity of 93%, and AUC of 0.978. Median relative expression of miR-371a-3p in viable GCT patients was >6,800-fold higher than in patients lacking viable GCT. MiR-371a-3p levels correlated with composite stage (CS) (p=0.006), and, among CS I patients, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p < 0.0001). Six patients received orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable GCT by the miR-371a-3p test.
Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional STMs to aid clinical decision-making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation.