Biology subjects

Menon, M.

Publications and source records attributed to Menon, M..

25 records · Page 2Linked to original sources

bioRxiv2019

The Impact of a Wireless Audio System on Communication in Robotic-Assisted Laparoscopic Surgery: A Prospective Controlled Trial

BackgroundRobotic surgery presents a challenge to effective teamwork and communication in the operating theatre (OR). Our objective was to evaluate the effect of using a wireless audio headset device on communication, efficiency and patient outcome in robotic surgery.\n\nMethods and findingsA prospective controlled trial of team members participating in gynecologic and urologic robotic procedures between January and March 2015. In the first phase, all surgeries were performed without headsets (control), followed by the intervention phase where all team members used the wireless headsets. Noise levels were measured during both phases. After each case, all team members evaluated the quality of communication, performance, teamwork and mental load using a validated 14-point questionnaire graded on a 1-10 scale. Higher overall scores indicated better communication and efficiency. Clinical and surgical data of all patients in the study were retrieved, analyzed and correlated with the survey results.\n\nThe study included 137 procedures, yielding 843 questionnaires with an overall response rate of 89% (843/943). Self-reported communication quality was better in cases where headsets were used (113.0 {+/-} 1.6 vs. 101.4 {+/-} 1.6; p < .001). Use of headsets reduced the percentage of time with a noise level above 70 dB at the console (8.2% {+/-} 0.6 vs. 5.3% {+/-} 0.6, p < .001), but had no significant effect on length of surgery nor postoperative complications.\n\nConclusionsThe use of wireless headset devices improved quality of communication between team members and reduced the peak noise level in the robotic OR.

scientific communication and education↗

bioRxiv2019

Clonal evaluation of early onset prostate cancer by expression profiling of ERG, SPINK1, ETV1, and ETV4 on whole mount radical prostatectomy tissue

Expression profiles of ETS related genes and SPINK1 in early onset prostate cancer have not been thoroughly explored. We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55yrs) and characterized the expression of ERG, SPINK1, ETV1 and ETV4 by dual immunohistochemistry and dual RNA in-situ hybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence and pathological variables using whole mount radical prostatectomy tissue were collected. 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans. Positive family history of prostate cancer was observed in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/ml (mean 7.04). Follow-up period ranged from 1 to 123.7 months (Mean 30.3). Biochemical recurrence was encountered in 8/151 (5%). ERG overexpression was observed in 85/151 (56%) cases, followed by SPINK1 in 61/151 (40%), ETV1 in 9/149 (6%), and ETV4 in 4/141 (3%). There were 25/151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients ([≤] 45 years old) (76% vs. 49%, p = 0.002213), Caucasian men (71% vs. 41% p = 0.000707), organ-confined tumors (64% vs. 33%, p = 0.00079), and tumors of Grade Groups 1 and 2 (62% vs. 26%, p = 0.008794). SPINK1 overexpression was more in African American men (68% vs. 26%, p = 0.00008), in tumors with high tumor volume (> 20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors. This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.

pathology↗

bioRxiv2019

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

cancer biology↗

bioRxiv2018

Virus-like vesicles expressing multiple antigens for immunotherapy of chronic hepatitis B

Infection with hepatitis B virus (HBV) can initiate chronic hepatitis and liver injury, eventually progressing to liver fibrosis or cancer and causing more than 600,000 deaths each year worldwide. Current treatments for chronic hepatitis B, relying on nucleoside antivirals and interferon, are inadequate and leave an unmet need for immunotherapeutic approaches. This report describes virus-like vesicles (VLV), a form of self-amplifying RNA replicons, which express multiple HBV antigens (polymerase, core, and middle surface) from a single vector (HBV-VLV). The HBV-VLV induces HBV-specific T cell responses to all three HBV antigens. Immunization of naive mice with the multiantigen HBV-VLV renders them resistant to acute challenge with HBV delivered by adeno-associated virus (AAV). Using a chronic model of HBV infection by AAV delivery of HBV, we demonstrate immunotherapeutic potential of the multiantigen HBV-VLV in combination with DNA booster immunization, as 40% of the HBV-VLV-treated mice showed a decline of the serum HBV surface antigen below the detection limit and marked reduction in liver HBV RNA accompanied by induction of HBsAg-specific CD8 T cells. These results warrant further evaluation of multiantigen HBV-VLV for immunotherapy of chronic hepatitis B. IMPORTANCEMore than 240 million people worldwide are chronically infected with hepatitis B virus. Current therapies are not sufficiently effective and are often beyond reach in the developing world. We describe a virus-like vesicle-based immunotherapeutic vaccine that expresses three major antigens of hepatitis B virus as a self-amplifying RNA replicon. By incorporating three HBV antigens in a single vaccine, we ensure broad T cell responses. We demonstrate that immunization with this vaccine protects mice from hepatitis B virus in a model of acute challenge. Importantly, treatment with this vaccine shows 40% efficacy in a mouse model of chronic hepatitis B. Thus, this study paves the way for evaluation of the multi-antigen virus-like vesicles as a tool for immunotherapy of chronic hepatitis B.

immunology↗

bioRxiv2017

Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

PARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 \"tag, mutate and enrich\" mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

cancer biology↗

bioRxiv2017

The genomics of local adaptation in trees: Are we out of the woods yet?

There is substantial interest in uncovering the genetic basis of the traits underlying adaptive responses in tree species, as this information will ultimately aid conservation and industrial endeavors across populations, generations, and environments. Fundamentally, the characterization of such genetic bases is within the context of a genetic architecture, which describes the mutlidimensional relationship between genotype and phenotype through the identification of causative variants, their relative location within a genome, expression, pleiotropic effect, environmental influence, and degree of dominance, epistasis, and additivity. Here, we review theory related to polygenic local adaptation and contextualize these expectations with methods often used to uncover the genetic basis of traits important to tree conservation and industry. A broad literature survey suggests that most tree traits generally exhibit considerable heritability, that underlying quantitative genetic variation (QST) is structured more so across populations than neutral expectations (FST) in 69% of comparisons across the literature, and that single-locus associations often exhibit small estimated per-locus effects. Together, these results suggest differential selection across populations often acts on tree phenotypes underlain by polygenic architectures consisting of numerous small to moderate effect loci. Using this synthesis, we highlight the limits of using solely single-locus approaches to describe underlying genetic architectures and close by addressing hurdles and promising alternatives towards such goals, remark upon the current state of tree genomics, and identify future directions for this field. Importantly, we argue, the success of future endeavors should not be predicated on the shortcomings of past studies and will instead be dependent upon the application of theory to empiricism, standardized reporting, centralized open-access databases, and continual input and review of the communitys research.

evolutionary biology↗

bioRxiv2017

The role of hybridization during ecological divergence of southwestern white pine (Pinus strobiformis) and limber pine (P. flexilis)

Interactions between extrinsic factors, such as disruptive selection, and intrinsic factors, such as genetic incompatibilities among loci, can contribute to the maintenance of species boundaries. The relative roles of these factors in the establishment of reproductive isolation can be examined using species pairs characterized by gene flow throughout their divergence history. We investigated the process of speciation and the maintenance of species boundaries between Pinus strobiformis and P.flexilis. Utilizing ecological niche modeling, demographic modeling, and genomic cline analyses, we illustrated a history of divergence with continuous gene flow between these species. We found an abundance of advanced generation hybrids and a lack of loci exhibiting large allele frequency differences across the hybrid zone. Additionally, we found evidence for climate-associated variation in the hybrid index and niche divergence between parental species and the hybrid zone. Our results are consistent with extrinsic factors, such as climate, being an important isolating mechanism for these species. A buildup of intrinsic incompatibilities and of co-adapted gene complexes is also apparent in our results, although these appear to be in the earliest stages of development. This supports previous work in coniferous species demonstrating the importance of extrinsic factors in creating and enforcing species boundaries. Overall, we lend support to the hypothesis that varying strengths and directions of selection pressures across the long lifespans of conifers, in combination with their life history strategies, delay the evolution of strong intrinsic incompatibilities.

evolutionary biology↗