Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer.

BACKGROUND Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification. METHODS We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays. FINDINGS We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts. INTERPRETATION Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC

Honey bee foraging distance depends on month and forage type

To investigate the distances at which honey bee foragers collect nectar and pollen, we analysed 5,484 decoded waggle dances made to natural forage sites to determine monthly foraging distance for each forage type. Firstly, we found significantly fewer overall dances made for pollen (16.8 %) than for non-pollen, presumably nectar (83.2 %; P < 2.2 × 10−23). When we analysed distance against month and forage type, there was a significant interaction between the two factors, which demonstrates that in some months, one forage type is collected at farther distances, but this would reverse in other months. Overall, these data suggest that distance, as a proxy for forage availability, is not significantly and consistently driven by need for one type of forage over the other

Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.

Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype. Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis. Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

A gossypiboma (foreign body granuloma) mimicking a residual odontogenic cyst in the mandible: a case report

<p>Abstract</p> <p>Introduction</p> <p>Gossypiboma (foreign body granuloma) in the tooth socket as a complication of tooth removal is rare. Several cases of gossypiboma have been reported after orthopedic, abdominal, otorhinolaryngology, or plastic surgery, but there has been only one reported case after oral surgery.</p> <p>Case presentation</p> <p>A 42-year-old Caucasian German-speaking Swiss woman applied to our clinic for removal of her right mandibular first molar. Her right mandibular third molar had been removed seven years ago. Post-operatively, she complained of pain and foreign body sensation for six months in the area of the removed tooth. A panoramic radiograph of our patient showed a defined and oval radiolucent area in the socket of the right mandibular third molar evoking a residual cyst. An operation was planned to remove the cyst-like lesion. During surgery, a foreign body composed of gauze was found in the right mandibular third molar region. The histological findings were compatible with a foreign body reaction around gauze.</p> <p>Conclusion</p> <p>Retained gauze must be considered if patients complain of pain and foreign body sensation after tooth removal. The use of gauze with radio-opaque markers and extensive irrigation of the socket with saline to remove gauze fragments can avoid this mishap.</p

Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate

BACKGROUND: This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD). METHODS: Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA). RESULTS: The most common adverse events were elevated blood pressure (46.7%), QTc prolongation (23.3%), elevated temperature (13.3%), and headache (10%), followed by nausea and eye injection (6.7%). There were no adverse events that were considered severe in intensity and none resulted in discontinuation of treatment. There was reduction of the excess foveal thickness by 24.15% at end of treatment period and by 43.75% at end of the two-month follow-up (p = 0.674 and 0.161, respectively). BCVA remained stable throughout the treatment and follow-up periods. CONCLUSIONS: The safety profile of intravenous CA4P was consistent with that reported in oncology trials of CA4P and with the class effects of vascular disruptive agents; however, the frequency of adverse events was different. There are evidences to suggest potential efficacy of CA4P in neovascular AMD. However, the level of systemic safety and efficacy indicates that systemic CA4P may not be suitable as an alternative monotherapy to current standard-of-care therapy

Surgical Resection of Primary Tumors Provides Survival Benefits for Lung Cancer Patients With Unexpected Pleural Dissemination

Background: Surgery is not generally recommended for non-small cell lung cancer (NSCLC) patients with malignant pleural dissemination (PD). However, in some cases, PD is found unexpectedly during surgery. There is no consensus on whether surgical intervention can provide survival benefit for them. We investigated the role of surgery in NSCLC patients with unexpected PD by a cohort study.Methods: Clinical data of consecutive patients who intended to undergo radical surgery for NSCLC between January 2010 and December 2015 at Shanghai Chest Hospital and Huadong Hospital were collected from a lung cancer database. Patients diagnosed with unexpected malignant pleural nodules intraoperatively were enrolled in this retrospective study.Results: A total of 181 NSCLC patients were diagnosed with unexpected malignant PD intraoperatively and confirmed with postoperatively histological examinations. Out of these, 80 (44.2%) patients received pleural nodule biopsies alone, and 101 (55.8%) received primary tumor resection (47 with sublobar resection and 54 with lobectomy). The median progression-free survival and overall survival for all patients were 13 and 41 months respectively. Patients in the resection group had significantly better progression-free survival (19.0 vs. 10.0 months, P &lt; 0.0001) and overall survival (48.0 vs. 33.0 months, P &lt; 0.0001) than patients in the biopsy group. In the resection group, there was no statistical difference between patients with sublobar resection and lobectomy (P = 0.34). Univariate and multivariate analyses identified primary tumor resection, targeted adjuvant therapy, and tumor size (≤ 3 cm) as independent prognostic factors.Conclusions: NSCLC patients with unexpected intraoperative PD potentially benefited from surgical resection of the primary tumor and multidisciplinary targeted therapy, particularly when tumor size did not exceed 3 cm. Our data demonstrated that the resection type was not associated with survival differences, which remains to be defined with a larger sample size

MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis

Primary pyogenic spondylitis following kyphoplasty: a case report

<p>Abstract</p> <p>Introduction</p> <p>Only ten cases of primary pyogenic spondylitis following vertebroplasty have been reported in the literature. To the best of our knowledge, we present the first reported case of primary pyogenic spondylitis and spondylodiscitis caused by kyphoplasty.</p> <p>Case presentation</p> <p>A 72-year old Caucasian man with an osteoporotic compression fracture of the first lumbar vertebra after kyphoplasty developed sensory incomplete paraplegia below the first lumbar vertebra. This was caused by myelon compression following pyogenic spondylitis with a psoas abscess. Computed tomography guided aspiration of the abscess cavity yielded group C <it>Streptococcus</it>. The psoas abscess was percutaneously drained and laminectomy and posterior instrumentation with an internal fixator from the eleventh thoracic vertebra to the fourth lumbar vertebra was performed. In a second operation, corpectomy of the first lumbar vertebra with cement removal and fusion from the twelfth thoracic vertebra to the second lumbar vertebra with a titanium cage was performed. Six weeks postoperatively, the patient was pain free with no neurologic deficits or signs of infection.</p> <p>Conclusion</p> <p>Pyogenic spondylitis is an extremely rare complication after kyphoplasty. When these patients develop recurrent back pain postoperatively, the diagnosis of pyogenic spondylitis must be considered.</p