Clinical-grade Detection of Microsatellite Instability in Colorectal Tumors by Deep Learning

Background and Aims: Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on routine histology slides faster and cheaper than molecular assays. But clinical application of this technology requires high performance and multisite validation, which have not yet been performed. Methods: We collected hematoxylin and eosin-stained slides, and findings from molecular analyses for MSI and dMMR, from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (n=6406 specimens) and validated in an external cohort (n=771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC). Results: The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound 0.91, upper bound 0.93) and an AUPRC of 0.63 (range, 0.59–0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC curve of 0.95 (range, 0.92–0.96) without image-preprocessing and an AUROC curve of 0.96 (range, 0.93–0.98) after color normalization. Conclusions: We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using hematoxylin and eosin-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens

Effects of p38α/β inhibition on Acute Lymphoblastic Leukemia (ALL) proliferation and survival <em>in vivo</em>.

P38α/β has been described as a tumor suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, p38α/β also regulates other cellular processes. Here, we describe a role of p38α/β as a regulator of ALL proliferation and survival in experimental ALL models. We also report first evidence that p38α/β phosphorylation is associated with the occurrence of relapses in TEL-AML1 positive leukemia. First, in vitro experiments show that p38α/β signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate p38α/β in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that p38α/β inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38α strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo p38α/β phosphorylation is associated with an inferior long-term relapse-free survival. We propose p38α/β as a mediator of proliferation and survival in ALL and show first preclinical evidence for p38α/β inhibition as an adjunct approach to conventional therapies

The Impact of Cancer-Associated Fibroblasts on the Biology and Progression of Colorectal Carcinomas

(1) Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. Cancer-associated fibroblasts (CAFs) are major components of CRC’s tumour microenvironment (TME), but their biological background and interplay with the TME remain poorly understood. This study investigates CAF biology and its impact on CRC progression. (2) The cohort comprises 155 cases, including CRC, with diverse localizations, adenomas, inflammations, and controls. Digital gene expression analysis examines genes associated with signalling pathways (MAPK, PI3K/Akt, TGF-β, WNT, p53), while next-generation sequencing (NGS) determines CRC mutational profiles. Immunohistochemical FAP scoring assesses CAF density and activity. (3) FAP expression is found in 81 of 150 samples, prevalent in CRC (98.4%), adenomas (27.5%), and inflammatory disease (38.9%). Several key genes show significant associations with FAP-positive fibroblasts. Gene set enrichment analysis (GSEA) highlights PI3K and MAPK pathway enrichment alongside the activation of immune response pathways like natural killer (NK)-cell-mediated cytotoxicity via CAFs. (4) The findings suggest an interplay between CAFs and cancer cells, influencing growth, invasiveness, angiogenesis, and immunogenicity. Notably, TGF-β, CDKs, and the Wnt pathway are affected. In conclusion, CAFs play a significant role in CRC and impact the TME throughout development

Carboxylate Groups in a 90 degrees Arrangement: 1,3-Allenedicarboxylic Acid and Its Alkali Metal and Thallium(I) Coordination Compounds

With its two carboxylate functions arranged in an 90 degrees angle, 1,3-allenedicarboxylic acid (point group C-1) possesses a symmetry distinguished from all other dicarboxylic acids which are generally utilized as linker compounds in coordination polymers or MOFs. Crystal structures of coordination compounds with the 1,3-allenedicarboxylate dianion are reported herein for the first time. The diacid was converted with metal carbonates M2CO3 to furnish the crystalline lithium, sodium, rubidium, cesium and thallium(I) compounds. In the solid state, their structures differ significantly. Common motif is the dianion, which is linked by the cations to columns, layers or strands. The sodium compound exhibits an unusual structural feature: One of the three crystallographically different sodium ions coordinates to four instead of six oxygen atoms with seesaw geometry, i.e. two equatorial positions of an octahedral coordination are unoccupied. Thus, an almost linear (179 degrees) O-Na-O unit holds two ancillary oxygen atoms with perpendicular geometry (angles 94 degrees and 95 degrees)