A STAT3 protein complex required for mitochondrial mRNA stability and cancer.

Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.

MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance. METHODS: Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC. RESULTS: MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival. CONCLUSIONS: MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.

Evaluation of Immediately Loaded Parallel Conical Connection Implants with Platform Switch in the Maxillary Esthetic Zone: A Prospective Clinical Study.

AIM: To assess immediately loaded parallel conical connection (Nobel Biocare) implants with platform switch design in the maxillary esthetic zone for soft and hard tissue changes. MATERIALS AND METHODS: A total of 20 patients (n = 20) underwent prosthetic replacement of the missing maxillary anterior tooth, with an immediately loaded parallel conical connection implant (Noble Biocare, Sweden) having a platform switch design. The size of the implant was 3.75 mm in width and 13 mm in length for all patients and placement followed a standardized surgical protocol. Postoperatively, acrylic provisionalization was done within 48 hours followed by a definitive zirconia prosthesis in the 3rd month. Clinically and radiographically, the implants were evaluated for hard tissue (bone density, implant stability, crestal bone loss) and soft tissue changes (mucosal thickness-MT, sulcus probing depth-PD, bleeding on probing-BOP, width of keratinized gingiva-KG) at baseline till 36 months with follow-up intervals after loading. RESULTS: All patients showed uneventful healing. The difference in implant stability and density scores was significant (p <0.05*) from baseline to 36 months indicating bone formation and osseointegration of the implant. Bleeding on probing was not observed, and probing depth remained within the acceptable range (≤5 mm) at all time intervals after loading. The marginal bone loss was minimal (≤0.2 mm annually) with the absence of implant mobility and without any peri-implant radiolucency. The thickness of the gingiva (3.47 ± 0.34 mm) and width of keratinized gingiva (2.46 ± 0.39 mm) remained within reasonable limits at the 36th month with acceptable esthetic appearance. CONCLUSION: In the present study, immediate loading of Nobel parallel conical connection implant in the maxillary anterior region provided adequate primary stability, minimal marginal bone loss, and increased bone density indicating earlier osseointegration. Decreased probing depth, absence of bleeding on probing, and adequate tissue collar at the neck showed better soft tissue emergence in the esthetic zone. The platform switch design demonstrated promising results and therefore can be used as an alternative to the conventional method. CLINICAL SIGNIFICANCE: The present study results suggest that parallel conical connection implants (Nobel Biocare) with TiUnite surface, built-in platform switch combined with conical connection interface, parallel walled body, tapered apex, and double threads from tip to platform are all designed to provide high primary stability and support immediate function protocol, hence can be used flexibly in different bone densities.

Lineage-restricted neoplasia driven by Myc defaults to small cell lung cancer when combined with loss of p53 and Rb in the airway epithelium.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by loss of function TP53 and RB1 mutations in addition to mutations in other oncogenes including MYC. Overexpression of MYC together with Trp53 and Rb1 loss in pulmonary neuroendocrine cells of the mouse lung drives an aggressive neuroendocrine low variant subtype of SCLC. However, the transforming potential of MYC amplification alone on airway epithelium is unclear. Therefore, we selectively and conditionally overexpressed MYC stochastically throughout the airway or specifically in neuroendocrine, club, or alveolar type II cells in the adult mouse lung. We observed that MYC overexpression induced carcinoma in situ which did not progress to invasive disease. The formation of adenoma or SCLC carcinoma in situ was dependent on the cell of origin. In contrast, MYC overexpression combined with conditional deletion of both Trp53 and Rb1 exclusively gave rise to SCLC, irrespective of the cell lineage of origin. However, cell of origin influenced disease latency, metastatic potential, and the transcriptional profile of the SCLC phenotype. Together this reveals that MYC overexpression alone provides a proliferative advantage but when combined with deletion of Trp53 and Rb1 it facilitates the formation of aggressive SCLC from multiple cell lineages.

Genetic Modulators of Traumatic Brain Injury in Animal Models and the Impact of Sex-Dependent Effects.

Traumatic brain injury (TBI) is a major health problem causing disability and death worldwide. There is no effective treatment, due in part to the complexity of the injury pathology and factors affecting its outcome. The extent of brain injury depends on the type of insult, age, sex, lifestyle, genetic risk factors, socioeconomic status, other co-injuries, and underlying health problems. This review discusses the genes that have been directly tested in TBI models, and whether their effects are known to be sex-dependent. Sex differences can affect the incidence, symptom onset, pathology, and clinical outcomes following injury. Adult males are more susceptible at the acute phase and females show greater injury in the chronic phase. TBI is not restricted to a single sex; despite variations in the degree of symptom onset and severity, it is important to consider both female and male animals in TBI pre-clinical research studies.