Molecular Atlas of HER2+ Breast Cancer Cells Treated with Endogenous Ligands: Temporal Insights into Mechanisms of Trastuzumab Resistance.

Trastuzumab therapy in HER2+ breast cancer patients has mixed success owing to acquired resistance to therapy. A detailed understanding of downstream molecular cascades resulting from trastuzumab resistance is yet to emerge. In this study, we investigate the cellular mechanisms underlying acquired resistance using trastuzumab-sensitive and -resistant cancer cells (BT474 and BT474R) treated with endogenous ligands EGF and HRG across time. We probe early receptor organization through microscopy and signaling events through multiomics measurements and assess the bioenergetic state through mitochondrial measurements. Integrative analyses of our measurements reveal significant alterations in EGF-treated BT474 HER2 membrane dynamics and robust downstream activation of PI3K/AKT/mTORC1 signaling. EGF-treated BT474R shows a sustained interferon-independent activation of the IRF1/STAT1 cascade, potentially contributing to trastuzumab resistance. Both cell lines exhibit temporally divergent metabolic demands and HIF1A-mediated stress responses. BT474R demonstrates inherently increased mitochondrial activity. HRG treatment in BT474R leads to a pronounced reduction in AR expression, affecting downstream lipid metabolism with implications for treatment response. Our results provide novel insights into mechanistic changes underlying ligand treatment in BT474 and BT474R and emphasize the pivotal role of endogenous ligands. These results can serve as a framework for furthering the understanding of trastuzumab resistance, with therapeutic implications for women with acquired resistance.

Temporal transcriptional control of neural induction in human induced pluripotent stem cells.

Introduction: Neural induction of human induced pluripotent stem cells represents a critical switch in cell state during which pluripotency is lost and commitment to a neural lineage is initiated. Although many of the key transcription factors involved in neural induction are known, we know little of the temporal and causal relationships that are required for this state transition. Methods: Here, we have carried out a longitudinal analysis of the transcriptome of human iPSCs undergoing neural induction. Using the temporal relationships between the changing profile of key transcription factors and subsequent changes in their target gene expression profiles, we have identified distinct functional modules operative throughout neural induction. Results: In addition to modules that govern loss of pluripotency and gain of neural ectoderm identity, we discover other modules governing cell cycle and metabolism. Strikingly, some of these functional modules are retained throughout neural induction, even though the gene membership of the module changes. Systems analysis identifies other modules associated with cell fate commitment, genome integrity, stress response and lineage specification. We then focussed on OTX2, one of the most precociously activated transcription factors during neural induction. Our temporal analysis of OTX2 target gene expression identified several OTX2 regulated gene modules representing protein remodelling, RNA splicing and RNA processing. Further CRISPRi inhibition of OTX2 prior to neural induction promotes an accelerated loss of pluripotency and a precocious and aberrant neural induction disrupting some of the previously identified modules. Discussion: We infer that OTX2 has a diverse role during neural induction and regulates many of the biological processes that are required for loss of pluripotency and gain of neural identity. This dynamical analysis of transcriptional changes provides a unique perspective of the widespread remodelling of the cell machinery that occurs during neural induction of human iPSCs.

Management and outcomes of ureteroceles in children: An experience of 25 years.

INTRODUCTION: Ureterocele is a rare urogenital malformation. The treatment is variable and complicated as it depends on several factors. The aim of this study was to evaluate the management and outcomes of children with ureterocele and to compare single system and duplex system ureteroceles. MATERIALS AND METHODS: A retrospective study was conducted and all patients with ureterocele operated from January 1992 to December 2018 were included. The records of those included were assessed, and a detailed case record sheet was filled. The outcome parameters assessed were the persistence of symptoms and additional surgical procedure performed. RESULTS: Forty-seven patients (28 boys and 19 girls) with a median age of presentation of 21 months were included. Four patients had bilateral ureterocele. Overall, 51 renal units with ureterocele were studied. Twenty renal units of the 31 renal units with duplex system underwent cystoscopic decompression, and of these, 8 (40%) needed a second procedure. Fourteen renal units of the remaining 20 renal units with single system underwent cystoscopy and decompression, and of these, 1 (7%) required another procedure (P = 0.024). Sixteen renal units had ectopic ureterocele, of which 9 (56%) underwent heminephrectomy/nephrectomy. Intravesical ureterocele was present in 35 renal units, of which only 2 (5.7%) underwent nephrectomy or heminephrectomy (P < 0.001). CONCLUSION: Duplex system ureteroceles are more likely to require a second procedure following an endoscopic puncture. Units with ectopic ureterocele were more likely to need nephrectomy.

Giant Gastric Polyp in Peutz-Jeghers Syndrome: Report of a Case.

Peutz-Jeghers syndrome (PJS) is inherited as an autosomal dominant disorder presenting as hamartomatous polyps in the small bowel, mucocutaneous pigmentation and with a predisposition to develop cancer. We report a case of PJS, with an adenomatous giant gastric polyp. The purpose is to highlight that adenomatous giant gastric polyp may be an extremely rare presentation of PJS. Awareness of this possibility will help us in not missing out these atypical cases of PJS.

Cardiac tissue engineering and regeneration using cell-based therapy.

Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells.