Mcl-1 Inhibition Modulates ERK-Mediated Resistance in Multiple Myeloma

Novel multiple myeloma (MM) treatments have significantly improved over the previous several decades, primarily on account of targeting bone marrow microenvironment (BMM) pathways. However, drug resistance and patient relapse remain major clinical problems. The role of BMM in the upregulation of anti-apoptotic protein Mcl-1 is well documented. The Mcl-1 protein plays a critical role in the progression and acquired drug resistance in MM. The regulation of Mcl-1, a protein characterized by a short half-life, from transcription to degradation is crucial for understanding its role in cell survival. The GSK3β and Erk play important role in the stability of Mcl-1. Also, overexpression of phospho Erk is associated with the acquired resistance. In this study, we investigated Mcl-1 regulation, focusing on transcriptional and post-translational modifications and their impact on protein stability in Mcl-1 inhibitor ( KS18) treated cells. The small molecule inhibitor KS18 induces Mcl-1Ser159/Thr163 phosphorylation and ubiquitination resulting in a sharp decline in Mcl-1 protein levels. Furthermore, we assessed the effects of the KS18 in a combination with ERK inhibitors on cell viability and found that blocking the Mcl-1 stabilization mechanism improves the effectiveness and potency of KS18. Furthermore, we compared KS18 to different classes of chemotherapeutic agents, such as GSK3β/α inhibitor (LY209031), ERK inhibitor (SEH77272), MEK inhibitor (PD18435), and Akt inhibitor (AZD5363). Interestingly, we found KS18 more potent than other agents. Combined, our results propose a strong rationale for novel combination therapies using selective KS18 and ERK inhibitors, which have the potential to markedly improve the outcome of MM treatment. This may also address one of the major clinical problems, drug resistance, and enhance the use of existing drugs

Integrating transcriptomic and proteomic data for accurate assembly and annotation of genomes

© 2017 Wong et al.; Published by Cold Spring Harbor Laboratory Press. Complementing genome sequence with deep transcriptome and proteome data could enable more accurate assembly and annotation of newly sequenced genomes. Here, we provide a proof-of-concept of an integrated approach for analysis of the genome and proteome of Anopheles stephensi, which is one of the most important vectors of the malaria parasite. To achieve broad coverage of genes, we carried out transcriptome sequencing and deep proteome profiling of multiple anatomically distinct sites. Based on transcriptomic data alone, we identified and corrected 535 events of incomplete genome assembly involving 1196 scaffolds and 868 protein-coding gene models. This proteogenomic approach enabled us to add 365 genes that were missed during genome annotation and identify 917 gene correction events through discovery of 151 novel exons, 297 protein extensions, 231 exon extensions, 192 novel protein start sites, 19 novel translational frames, 28 events of joining of exons, and 76 events of joining of adjacent genes as a single gene. Incorporation of proteomic evidence allowed us to change the designation of more than 87 predicted noncoding RNAs to conventional mRNAs coded by protein-coding genes. Importantly, extension of the newly corrected genome assemblies and gene models to 15 other newly assembled Anopheline genomes led to the discovery of a large number of apparent discrepancies in assembly and annotation of these genomes. Our data provide a framework for how future genome sequencing efforts should incorporate transcriptomic and proteomic analysis in combination with simultaneous manual curation to achieve near complete assembly and accurate annotation of genomes

Genomic Profiling of Advanced-Stage Oral Cancers Reveals Chromosome 11q Alterations as Markers of Poor Clinical Outcome

Identifying oral cancer lesions associated with high risk of relapse and predicting clinical outcome remain challenging questions in clinical practice. Genomic alterations may add prognostic information and indicate biological aggressiveness thereby emphasizing the need for genome-wide profiling of oral cancers. High-resolution array comparative genomic hybridization was performed to delineate the genomic alterations in clinically annotated primary gingivo-buccal complex and tongue cancers (n = 60). The specific genomic alterations so identified were evaluated for their potential clinical relevance. Copy-number changes were observed on chromosomal arms with most frequent gains on 3q (60%), 5p (50%), 7p (50%), 8q (73%), 11q13 (47%), 14q11.2 (47%), and 19p13.3 (58%) and losses on 3p14.2 (55%) and 8p (83%). Univariate statistical analysis with correction for multiple testing revealed chromosomal gain of region 11q22.1–q22.2 and losses of 17p13.3 and 11q23–q25 to be associated with loco-regional recurrence (P = 0.004, P = 0.003, and P = 0.0003) and shorter survival (P = 0.009, P = 0.003, and P 0.0001) respectively. The gain of 11q22 and loss of 11q23-q25 were validated by interphase fluorescent in situ hybridization (I-FISH). This study identifies a tractable number of genomic alterations with few underlying genes that may potentially be utilized as biological markers for prognosis and treatment decisions in oral cancers

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Convergence of a second-order scheme for non-local conservation laws

In this article, we present the convergence analysis of a second-order numerical scheme for traffic flow models that incorporate non-local conservation laws. We combine a MUSCL-type spatial reconstruction with strong stability preserving Runge-Kutta time-stepping to devise a fully discrete second-order scheme. The resulting scheme is shown to converge to a weak solution by establishing the maximum principle, bounded variation estimates and L1 Lipschitz continuity in time. Further, using a space-step dependent slope limiter, we prove its convergence to the entropy solution. We also propose a MUSCL-Hancock type second-order scheme which requires only one intermediate stage unlike the Runge-Kutta schemes and is easier to implement. The performance of the proposed second-order schemes in comparison to a first-order scheme is demonstrated through several numerical experiments

A Simple Technique Using Peri-Prosthetic Irrigation Improves Implant Salvage Rates in Immediate Implant-Based Breast Reconstruction

Background and objectives: Implant-related complications leading to implant loss contribute to major morbidity in immediate breast reconstruction (IBR). Various techniques have been advocated to improve rates of reconstruction salvage. The objective of our study was to assess if a peri-prosthetic irrigation system was an effective adjunct to the conventional wash-out technique in improving reconstruction salvage rates. Methods: The study included patients who had immediate implant-based breast reconstruction from January 2015 to November 2020. The conventional technique of reconstruction salvage, using debridement, wash-out, and implant/expander exchange with systemic use of antibiotics, was performed for patients undergoing exploration for infection until May 2019. A simple technique using a continuous peri-prosthetic irrigation system with vancomycin (1 g/L normal saline over 24 h) for 2 days was added as an adjunct to the conventional technique. Treatment details and clinical outcomes were compared between the groups. The study was approved by the Clinical Governance department. Results: During the study period, 335 patients underwent IBR. A total of 65 patients (19.4%) returned to the theatre due to post-operative complications, of which 45 (13.4%) were due to infection. A conventional technique was used in 38 (84.4%) patients, and peri-prosthetic irrigation was used as an adjunct in 7 patients (15.6%). A total of 16 (42.1%) in the conventional group and all 7 (100%) in the irrigation group had successful reconstruction salvage. No patients had complications due to antibiotic irrigation. Conclusions: The peri-prosthetic irrigation system is a simple, safe, and effective adjunct to conventional techniques in improving reconstruction salvage in IBR

Custom anatomic healing abutments

Dental implants with their increasing success rates and predictability of final outcome are fast becoming the treatment of choice for replacing missing teeth. Considering the success of immediate implant placement in reducing tissue loss and achieving good esthetic results, is making it a more popular treatment modality in implant dentistry. Understanding the management of gingival tissues in relation to implants to obtain maximum esthetics is of utmost importance. The use of provisional abutments and immediate temporization has a proven track record of their ability to produce optimal esthetics and to guide the tissue response during the healing phase. With careful patient selection and execution, customized healing abutments can provide an effective method to enhance the esthetic and emergence profile for anterior implant restorations

Laparoscopic cholecystectomy for cholelithiasis in children

<b>Aim:</b> To evaluate the role of laparoscopic cholecystectomy (LC) in the management of cholelithiasis in children. <b> Methods:</b> A retrospective review of our experience with LC for cholelithiasis at our institution, between April 2006 and November 2008, was done. Data included patient demographics, clinical history, hematological investigations, imaging studies, operative technique, postoperative complications, postoperative recovery, and final histopathological diagnosis. <b> Results:</b> During the study period of 32 months, 18 children (8 males and 10 females) with cholelithiasis were treated by LC. The mean age was 9.4 years (range 3-18). Seventeen children had symptoms of biliary tract disease and 1 child had incidentally detected cholelithiasis during an ultrasonography of abdomen for unrelated cause. Only 5 (27.8&#x0025;) children had definitive etiological risk factors for cholelithiasis and the remaining 13 (75.2&#x0025;) cases were idiopathic. Sixteen cases had pigmented gallstones and 2 had cholesterol gallstones. All the 18 patients underwent LC, 17 elective, and 1 emergency LC. The mean operative duration was 74.2 min (range 50-180). Postoperative complications occurred in 2 (11.1&#x0025;) patients. The average duration of hospital stay was 4.1 days (range 3-6). <b> Conclusion:</b> Laparoscopic chloecystectomy is a safe and efficacious treatment for pediatric cholelithiasis. The cause for increased incidence of pediatric gallstones and their natural history needs to be further evaluated