Endometrial cancer (EC) is the second most common malignancy of the female reproductive system worldwide. The updated EC classification emphasizes the significant role of various signaling pathways such as PIK3CA-PIK3R1-PTEN and RTK/RAS/β-catenin in EC pathogenesis. Some of these pathways are part of the EGF system signaling network, which becomes hyperactivated by various mechanisms and participates in cancer pathogenesis. In EC, the expression of ErbB receptors is significantly different, compared with the premenopausal and postmenopausal endometrium, mainly because of the increased transcriptional activity of ErbB encoding genes in EC cells. Moreover, there are some differences in ErbB-2 receptor profile among EC subgroups that could be explained by the alterations in pathophysiology and clinical behavior of various EC histologic subtypes. The fact that ErbB-2 receptor expression is more common in aggressive EC histologic subtypes (papillary serous and clear cell) could indicate a future role of ErbB-targeted therapies in well-defined EC subgroups with overexpression of ErbB receptors.

The unfolded protein response (UPR) mediated by IRE1/XBP1, PERK/eIF2α/ATF4, and ATF6/GRP78 governs tumor adaptation to hypoxia, nutrient deprivation, and therapy stress. In gynecologic malignancies (ovarian, endometrial, cervical), persistent endoplasmic reticulum (ER)-stress signaling underlies proliferation, invasion, immune evasion, and treatment resistance but also creates druggable liabilities. We conducted a narrative review of peer-reviewed literature indexed in MEDLINE (PubMed), Embase, Scopus, and Web of Science from inception through 13 September 2025. Search terms combined ER-stress/UPR pathways with gynecologic cancers. Eligible records included recent and high-quality preclinical, translational, and clinical studies, clinical trials, and high-quality reviews focused on UPR biology, biomarkers, or therapeutics. Data were synthesized by disease site and UPR branch. Across tumor types, UPR activation correlates with aggressive phenotypes and poorer outcomes. In epithelial ovarian cancer, GRP78/ATF6/PERK overexpression associates with inferior survival and chemoresistance, supporting their utility as biomarkers and therapeutic targets. Endometrial cancer demonstrates UPR gene-signature stratification of prognosis and immune infiltration, suggesting risk-adapted strategies. Cervical cancer leverages PERK/IRE1 signaling for therapy tolerance and dormancy. The tumor-immune interface is UPR-sensitive: CHOP and myeloid IRE1α signaling can dampen antitumor immunity, providing a rationale to pair UPR modulation with immunotherapy. Therapeutically, IRE1 RNase inhibitors (e.g., MKC-8866, B-I09), PERK/EIF2AK3 pathway modulators, protein-disulfide isomerase inhibition, and agents that trigger irrecoverable ER stress show preclinical efficacy, including synergy with platinum, poly (ADP-ribose) polymerase (PARP) inhibitors, HDAC6 blockers, and PD-1 inhibitors. Early clinical efforts investigating ER-stress-modulating combinations in platinum-resistant ovarian cancer highlight translational promise but remain preliminary. Thus, ER-stress/UPR signaling is a convergent, targetable axis in gynecologic cancers. Priorities include validating UPR-based prognostic signatures, defining context-specific vulnerabilities (e.g., genotype-informed IRE1/XBP1 dependence), and executing biomarker-driven clinical trials that combine UPR-targeted agents with standard chemotherapy, PARP inhibition, and immunotherapy to overcome resistance and improve patient outcomes.

Transcriptional enhancers are DNA regulatory elements that control the levels and spatiotemporal patterns of gene expression during development, homeostasis, and pathophysiological processes. Enhancer identification and characterization at the genome-wide scale rely on their structural characteristics, such as chromatin accessibility, binding of transcription factors and cofactors, activating histone modifications, 3D interactions with other regulatory elements, as well as functional characteristics measured by massively parallel reporter assays and sequence conservation approaches. Recently, machine learning approaches and particularly deep learning models (Enformer, BPNet, DeepSTARR, etc.) allow the prediction of enhancers, the impact of variants on their activity and the inference of transcription factor binding sites, leading, among others, to the construction of the first completely synthetic enhancers. We present the above computational tools and discuss their diverse applications towards cracking the enhancer regulatory code, which could have far-reaching ramifications for uncovering essential regulatory mechanisms and diagnosing and treating diseases. With an emphasis on sepsis, a leading cause of morbidity and mortality in hospitalized patients, we discuss computational approaches to identify sepsis-associated endotypes, circuits, and immune cell states and signatures characteristic of this condition, which could aid in developing novel therapies.

Plasminogen deficiency is an ultra-rare congenital condition with only a few reported cases worldwide, causing the formation of pseudo-membranous, fibrin-rich growths on mucosa throughout the body. In this case report, we present the rare case of a newborn presenting with multiple congenital central nervous system malformations due to severe plasminogen deficiency, in an otherwise completely unattended pregnancy. The mother was admitted to the emergency department due to the onset of labor. Upon routine ultrasound examination, marked macrocephaly and hydroanencephaly were observed. The fetus was delivered by selective cesarean section as fetal head dystocia was highly suspected. Unexpectedly, the neonatal examination immediately post-partum did not reveal any neurological deficits. An MRI was conducted, which confirmed the existence of congenital hydrocephalus, as well as holoprocencephaly, Dandy-Walker malformation, and anatomical anomalies of the fourth ventricle. Specialized further laboratory testing pinpointed severe plasminogen deficiency as the underlying condition. The neonate underwent ventriculoperitoneal shunt placement in an attempt to alleviate the increased intracerebral pressure and survived at least to six months of age, at the time this manuscript was written.