Injectable Self-Oxygenating Cardio-Protective and Tissue Adhesive Silk-Based Hydrogel for Alleviating Ischemia After Mi Injury.

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicine remains challenging. Here, a combinatorial strategy for cardiac repair by developing cardioprotective and oxygenating hybrid hydrogels that locally sustain the release of stromal cell-derived factor-1 alpha (SDF) and oxygen for simultaneous activation of neovascularization at the infarct area is presented. A sustained release of oxygen and SDF from injectable, mechanically robust, and tissue-adhesive silk-based hybrid hydrogels is achieved. Enhanced endothelialization under normoxia and anoxia is observed. Furthermore, there is a marked improvement in vascularization that leads to an increment in cardiomyocyte survival by ≈30% and a reduction of the fibrotic scar formation in an MI animal rodent model. Improved left ventricular systolic and diastolic functions by ≈10% and 20%, respectively, with a ≈25% higher ejection fraction on day 7 are also observed. Therefore, local delivery of therapeutic oxygenating and cardioprotective hydrogels demonstrates beneficial effects on cardiac functional recovery for reparative therapy.

A Novel Superpixel Approach to the Tumoral Microenvironment in Colorectal Cancer.

Colorectal cancer (CRC) is the most common malignancy of the gastrointestinal tract. The stroma and the tumoral microenvironment (TME) represent ecosystem-like biological networks and are new frontiers in CRC. The present study demonstrates the use of a novel machine learning-based superpixel approach for whole slide images to unravel this biology. Findings of significance include the association of low proportionated stromal area, high immature stromal percentage, and high myxoid stromal ratio (MSR) with worse prognostic outcomes in CRC. Overall, stromal computational markers outperformed all others at predicting clinical outcomes. MSR may be able to prognosticate patients independent of pathological stage, representing an optimal way to effectively prognosticate CRC patients which circumvents the need for more extensive molecular and/or computational profiling. The superpixel approaches to the TME demonstrated here can be performed by a trained pathologist and recorded during synoptic cancer reporting with appropriate quality assurance. Future clinical trials will have the ultimate say in determining whether we can better tailor the need for adjuvant therapy in patients with CRC.

Nature and Significance of Stromal Differentiation, PD-L1, and VISTA in GIST.

The role of stromal differentiation (SD), program death-ligand 1 (PD-L1), and v-domain Ig suppressor of T cell activation (VISTA) in gastrointestinal stromal tumor (GIST) is largely unknown. Looking forward, the assessment of SD and immune check point inhibition will become more ubiquitous in surgical pathology. Immature, myxoid stroma has been found to be a poor prognostic signature in many cancer subtypes (colon, breast, cervix, esophagus, stomach); although little is known regarding its significance in GIST. For immune check-point inhibition, studies have demonstrated expression to be associated with patient outcomes in numerous cancer subtypes. The present body of work aims to evaluate SD, PD-L1 and VISTA; both in terms of its nature and significance in a clinical setting. Here we found PD-L1 expression in immune cells (IC) and immature SD to be associated with worse cancer free survival, while positive VISTA expression was found to be associated with improved outcomes. High-grade, immature SD had the highest propensity for death/recurrence and was the only variable found to have prognostic significance on multivariate analysis. Our findings support the evaluation of SD, PD-L1 and VISTA in GIST, with clinical practice implications for pathologists. Ultimately, we hope our findings lead to improved prognostication, further optimization of therapeutics, and improved outcomes in a true clinical environment. For GIST, PD-L1 and VISTA could be both clinically relevant and targetable, while SD may be the answer to clinical heterogeneity.

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.

Understanding the role of indoleamine-2,3-dioxygenase and stromal differentiation in rare subtype endometrial cancer.

Endometrial cancer (EC) is a disease with good and poor prognostic subtypes. Dedifferentiated endometrial carcinoma (DEC), undifferentiated endometrial carcinoma (UEC), and clear cell endometrial carcinoma (CEC) are rare high-grade tumors, associated with a poor prognosis and high pathologic stage. Many studies have been performed on the programmed death-ligand 1 (PD-L1) axis mainly focus on endometrioid adenocarcinomas and little research has been done on rare subtypes. The present body of work aims to evaluate the role of indoleamine-2,3-dioxygenase (IDO-1) and stromal differentiation (SD), their correlation with clinicopathologic features and overall survival. Here we found that positive IDO-1 expression in immune cells correlated with worse disease-free survival (p = 0.02), recurrence (p = 0.03), high pathologic tumor stage (p = 0.024), lymph node metastasis (p = 0.028), and myometrial invasion (p = 0.03). Our findings suggest IDO-1 to be relevant in both MMR intact and deficient tumors; however, >20% immune cell staining was restricted to MMR deficient cancers. For the stroma, immature, myxoid differentiation was found to correlate with worse disease-free survival (p = 0.04). We also found the correlation between IDO-1 expression and immature stroma. Looking forward, IDO-1 could be promising for immunotherapy and SD could be the answer to clinical heterogeneity.

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.

Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.

Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management.

Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells.

Stromal cells are generally considered to be derived primarily from the host's normal mesenchymal stromal cells or bone marrow. However, the origins of stromal cells have been quite controversial. To determine the role of polyploidy in tumor development, we examined the fate of normal mullerian epithelial cells during the immortalization and transformation process by tracing the expression of SV40 large T antigen. Here we show that immortalized or HRAS-transformed mullerian epithelial cells contain a subpopulation of polyploid giant cells that grow as multicellular spheroids expressing hematopoietic markers in response to treatment with CoCl2. The immortalized or transformed epithelial cells can transdifferentiate into stromal cells when transplanted into nude mice. Immunofluorescent staining revealed expression of stem cell factors OCT4, Nanog, and SOX-2 in spheroid, whereas expression of embryonic stem cell marker SSEA1 was increased in HRAS-transformed cells compared with their immortalized isogenic counterparts. These results suggest that normal mullerian epithelial cells are intrinsically highly plastic, via the formation of polyploid giant cells and activation of embryonic stem-like program, which work together to promote the coevolution of neoplastic epithelial cells and multiple lineage stromal cells.