A prognostic matrix code defines functional glioblastoma phenotypes and niches.

Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a "matrix code" for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better patient survival, respectively. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles provide potential biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification which could be applied to optimize treatment responses.

A prognostic matrix code defines functional glioblastoma phenotypes and niches.

Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a "matrix code" for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better survival, respectively, of patients. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles may provide biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification to optimize treatment responses.

BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer.

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.

Precision Combination Therapies Based on Recurrent Oncogenic Coalterations.

Cancer cells depend on multiple driver alterations whose oncogenic effects can be suppressed by drug combinations. Here, we provide a comprehensive resource of precision combination therapies tailored to oncogenic coalterations that are recurrent across patient cohorts. To generate the resource, we developed Recurrent Features Leveraged for Combination Therapy (REFLECT), which integrates machine learning and cancer informatics algorithms. Using multiomic data, the method maps recurrent coalteration signatures in patient cohorts to combination therapies. We validated the REFLECT pipeline using data from patient-derived xenografts, in vitro drug screens, and a combination therapy clinical trial. These validations demonstrate that REFLECT-selected combination therapies have significantly improved efficacy, synergy, and survival outcomes. In patient cohorts with immunotherapy response markers, DNA repair aberrations, and HER2 activation, we have identified therapeutically actionable and recurrent coalteration signatures. REFLECT provides a resource and framework to design combination therapies tailored to tumor cohorts in data-driven clinical trials and preclinical studies. SIGNIFICANCE: We developed the predictive bioinformatics platform REFLECT and a multiomics- based precision combination therapy resource. The REFLECT-selected therapies lead to significant improvements in efficacy and patient survival in preclinical and clinical settings. Use of REFLECT can optimize therapeutic benefit through selection of drug combinations tailored to molecular signatures of tumors. See related commentary by Pugh and Haibe-Kains, p. 1416. This article is highlighted in the In This Issue feature, p. 1397.

Effects of modified atmosphere packaging on shelf life of Turkish delight (lokum).

Turkish delight is a sugar-based jellylike confection that has been produced for hundreds of years. In this study, four different modified atmospheres were created in order to extend the shelf life of Turkish delight. Microbiological analyses and sensory evaluations were conducted at the beginning of storage and at 7-day intervals thereafter. Microbiological analyses showed that the numbers of total mesophilic aerobic bacteria within samples stored in a modified atmosphere of 30% CO2 plus 70% N2 were lower than in the other modified atmospheres. According to sensory evaluations, the samples kept in a modified atmosphere of 50% CO2 plus 50% N2 were unacceptable after the 21st day of storage, whereas those kept in modified atmospheres of both 25% CO2 plus 75% N2 and 30% CO2 plus 70% N2 were found to be acceptable even after 30 days of storage.

Closure of skin incisions by 980-nm diode laser welding.

A 980-nm diode laser is proposed to be an alternative welding laser in dermatology due to its optimal penetration in tissue. An in vivo predosimetry study was done to estimate the optimal laser energy delivery conditions (6 W, 400 ms). Next, in vivo experiments were comparatively performed to examine healing of wounds closed either with suture or laser welding. One-centimeter-long, full-thickness incisions were done on the dorsal side of Wistar rats. Wounds were surgically removed at 1, 4, 7, 14, and 21 days postoperatively. Macroscopic examinations showed that welding had minimal scarring and a fine quality healing. According to histological (hematoxylin and eosin staining) results, change of epidermal thickness and granulation tissue formation through 21 days of healing period showed similarities in both methods. Epidermal thickness of welded wounds decreased from 62.46+/-6.87 microm (first day) to 36.49+/-0.92 microm (21st day) and that of sutured wounds decreased from 62.94+/-13.53 microm (first day) to 37.88+/-7.41 microm (21st day). At day 14, epidermal thickness of sutured wounds (61.20+/-6.60 microm) were higher than welded wounds (49.69+/-6.31 microm) (p<0.05). Besides, granulation values were greater for the sutured wounds but the difference was statistically significant (p<0.05) only for the seventh day (197,190.29+/-.89,554.96 microm(2) for sutured wounds, 138,433.1+/-51,077.17 microm(2) for welded wounds). Those differences indicate a faster recovery with laser welding. It is concluded that tissue welding with a 980-nm diode laser can be a good candidate for tissue welding applications with accelerated and improved healing, but further investigations are in progress for clinical use.

Low dose discontinued FK506 treatment enhances peripheral nerve regeneration.

FK506 has been reported to enhance nerve regeneration in various rodent models. However, both the immunosuppressive properties and potential side effects may preclude the broad clinical use of FK506 to speed nerve regeneration. In this study, we examined the nerve regenerative property of a low, nonimmunosuppressive dose (0.5 mg/kg/day) of FK506. Two treatment schedules (continuous versus discontinuous) were compared. Evaluations were perforrmed at 1, 2, and 3 months. The gastrocnemius muscle mass was significantly higher in treated groups compared with the untreated group at 3 months, and the total number of fibers, percentage of neural tissue, fiber density, and fiber diameter were greater in treated groups than in the untreated group. However, at 3 months there was no difference in these parameters between groups in which FK506 was administered continuously and those in which the drug was stopped at 2 months. This study confirms that daily administration of low dose FK506 enhances peripheral nerve recovery after transection injury.