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Introduction: Lack of evidence-based information regarding potential biological risks can result in inappropriate or excessive biosafety and biosecurity risk-reduction strategies. This can cause unnecessary damage and loss to the physical facilities, physical and psychological well-being of laboratory staff, and community trust. A technical working group from the World Organization for Animal Health (WOAH, formerly OIE), World Health Organization (WHO), and Chatham House collaborated on the Biosafety Research Roadmap (BRM) project. The goal of the BRM is the sustainable implementation of evidence-based biorisk management of laboratory activities, particularly in low-resource settings, and the identification of gaps in the current biosafety and biosecurity knowledge base. Methods: A literature search was conducted for the basis of laboratory design and practices for four selected high-priority subgroups of pathogenic agents. Potential gaps in biosafety were focused on five main sections, including the route of inoculation/modes of transmission, infectious dose, laboratory-acquired infections, containment releases, and disinfection and decontamination strategies. Categories representing miscellaneous, respiratory, bioterrorism/zoonotic, and viral hemorrhagic fever pathogens were created within each group were selected for review. Results: Information sheets on the pathogens were developed. Critical gaps in the evidence base for safe sustainable biorisk management were identified. Conclusion: The gap analysis identified areas of applied biosafety research required to support the safety, and the sustainability, of global research programs. Improving the data available for biorisk management decisions for research with high-priority pathogens will contribute significantly to the improvement and development of appropriate and necessary biosafety, biocontainment and biosecurity strategies for each agent.

Introduction: The SARS-CoV-2 virus emerged as a novel virus and is the causative agent of the COVID-19 pandemic. It spreads readily human-to-human through droplets and aerosols. The Biosafety Research Roadmap aims to support the application of laboratory biological risk management by providing an evidence base for biosafety measures. This involves assessing the current biorisk management evidence base, identifying research and capability gaps, and providing recommendations on how an evidence-based approach can support biosafety and biosecurity, including in low-resource settings. Methods: A literature search was conducted to identify potential gaps in biosafety and focused on five main sections, including the route of inoculation/modes of transmission, infectious dose, laboratory-acquired infections, containment releases, and disinfection and decontamination strategies. Results: There are many knowledge gaps related to biosafety and biosecurity due to the SARS-CoV-2 virus's novelty, including infectious dose between variants, personal protective equipment for personnel handling samples while performing rapid diagnostic tests, and laboratory-acquired infections. Detecting vulnerabilities in the biorisk assessment for each agent is essential to contribute to the improvement and development of laboratory biosafety in local and national systems.

India is an emerging basil essential oil producer in South-east Asia. Two high essential oil yielding hybrids, namely one inter specific hybrid between of O. basilicum and O. kilimandscharicum Gurke (HYBL-1) and another intraspecific hybrid of O. basilicum × O. basilicum (OBL-1) of basil were analyzed using GC, enantiomeric GC, NMR, enantio-GC–MS and GC–MS methods. Inter specific hybrid HYBL-1 contained high essential oil-rich in linalool (68.5%), camphor (8%), and 1,8-cineole (4.6%) as characteristic constituents among monoterpenoids, whereas β-caryophyllene (1.9%), germacrene D (1.0%), and epi-α-cadinol (1.9%) were the sesquiterpenoids at the Lucknow (North Indian conditions) and linalool (71.8%), camphor (9.4%) and 1,8-cineole (4.3%) at Hyderabad (South Indian conditions) locations. Intraspecific hybrid (OBL-1) possessed linalool (66.1%), 1,8-cineole (5.4%) and geraniol (8.6%) with sesquiterpenoids in low proportions. Inter specific hybrid HYBL-1 showed superiority over OBL-1 in the multi-location trials conducted at Lucknow and Hyderabad. Average mean performance of inter specific hybrid over locations was: herb yield 44.80 t/ha, oil content 0.63%, oil yield 188.50 kg/ha, linalool content 67.65%, camphor content 8.90% v/s OBL-1 herb yield 21.32 t/ha, oil content 0.53%, oil yield 97.50 kg/ha, linalool content 65.55%, camphor content 0.00%, respectively. The essential oil of these two hybrids subjected to enantiomer differentiation revealed a high enantiomeric excess for (3R) -(−)-linalool, whereas (1R)- (+)-camphor was recorded exclusively in inter specific hybrid. The extensive NMR experiments were performed to confirm constituents in these hybrids and found that NMR spectroscopy could also be an ideal tool for the differentiation of essential oils from commercial samples declared as natural.

Gene therapy has evolved over the past decade into a promising therapeutic class for treating many intractable diseases. Recombinant adeno-associated virus (AAV) is the most commonly used viral vector for delivering therapeutic genes. Independent of the manufacturing process for AAVs, the clinical materials are inherently heterogeneous and contain both empty and full capsids. Empty capsids can impact the safety and efficacy of AAV products and therefore their level needs to be controlled. Several analytical methods have been reported for this purpose. However, some of these methods have an insufficient assay range, or rely on instruments that cannot be readily implemented in a quality control (QC) environment. In this study, we describe a fast size exclusion chromatography (SEC) assay with dual-wavelength detection (SEC-DW) to directly determine the percent full capsids of AAV samples based on their peak area (PA) ratios. The two detection wavelengths selected to represent encapsidated transgenes and capsid proteins were 260 and 230 nm, respectively, instead of the conventionally used 260 and 280 nm. The use of 230 nm instead of 280 nm to monitor the contribution of the capsid protein results in a linear relationship between the PA260/PA230 ratio and the percent full capsids, unlike the nonlinear relationship observed when the PA260/PA280 ratio is used. As a result, the method exhibits a significantly extended assay range (up to 91% full capsids). The accuracy of the SEC-DW method was confirmed by comparing the results obtained against results from orthogonal high-resolution methods such as analytical ultracentrifugation (AUC) and cryo-electron microscopy and excellent agreement was obtained when common samples were analyzed using different methods. The SEC-DW method runs on a readily accessible high-performance liquid chromatography instrument platform, provides much higher assay throughput compared with AUC and electron microscopy, and can be implemented as a release method in a QC environment or used as a rapid screening tool to support process development and product understanding.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.

Introduction:Brucella melitensis and Bacillus anthracis are zoonoses transmitted from animals and animal products. Scientific information is provided in this article to support biosafety precautions necessary to protect laboratory workers and individuals who are potentially exposed to these pathogens in the workplace or other settings, and gaps in information are also reported. There is a lack of information on the appropriate effective concentration for many chemical disinfectants for this agent. Controversies related to B. anthracis include infectious dose for skin and gastrointestinal infections, proper use of personal protective equipment (PPE) during the slaughter of infected animals, and handling of contaminated materials. B. melitensis is reported to have the highest number of laboratory-acquired infections (LAIs) to date in laboratory workers. Methods: A literature search was conducted to identify potential gaps in biosafety and focused on five main sections including the route of inoculation/modes of transmission, infectious dose, LAIs, containment releases, and disinfection and decontamination strategies. Results: Scientific literature currently lacks information on the effective concentration of many chemical disinfectants for this agent and in the variety of matrices where it may be found. Controversies related to B. anthracis include infectious dose for skin and gastrointestinal infections, proper use of PPE during the slaughter of infected animals, and handling contaminated materials. Discussion: Clarified vulnerabilities based on specific scientific evidence will contribute to the prevention of unwanted and unpredictable infections, improving the biosafety processes and procedures for laboratory staff and other professionals such as veterinarians, individuals associated with the agricultural industry, and those working with susceptible wildlife species.

Introduction: Crimean Congo Hemorrhagic Fever (CCHF) virus and Lassa virus (LASV) are zoonotic agents regarded as high-consequence pathogens due to their high case fatality rates. CCHF virus is a vector-borne disease and is transmitted by tick bites. Lassa virus is spread via aerosolization of dried rat urine, ingesting infected rats, and direct contact with or consuming food and water contaminated with rat excreta. Methods: The scientific literature for biosafety practices has been reviewed for both these two agents to assess the evidence base and biosafety-related knowledge gaps. The review focused on five main areas, including the route of inoculation/modes of transmission, infectious dose, laboratory-acquired infections, containment releases, and disinfection and decontamination strategies. Results: There is a lack of data on the safe collection and handling procedures for tick specimens and the infectious dose from an infective tick bite for CCHF investigations. In addition, there are gaps in knowledge about gastrointestinal and contact infectious doses for Lassa virus, sample handling and transport procedures outside of infectious disease areas, and the contribution of asymptomatic carriers in viral circulation. Conclusion: Due to the additional laboratory hazards posed by these two agents, the authors recommend developing protocols that work effectively and safely in highly specialized laboratories in non-endemic regions and a laboratory with limited resources in endemic areas.

Mycoplasma hominis, a commensal of the genital tract, is a potential underestimated pathogen causing both genitourinary and extragenital infections including neonatal infections. Septic arthritis, prosthetic joint infection, central nervous system (CNS) infections, infective endocarditis and abscess formation are common extragenital infections associated mainly with immunocompromised patients. Mycoplasma hominis lipoproteins play an important role in pathogenicity and directly interact with the host immune system. Polymerase chain reaction (PCR) is the mainstay of diagnosis. Increasing resistance to tetracyclines and quinolones which are used for treatment, is a matter of global concern. We reviewed PubMed literature and Google search engine on the recent developments of association of Mycoplasma hominis with various diseases, pathogenesis, diagnosis and treatment.

Chalcones are an interesting class of compounds endowed with a plethora of biological activities beneficial to human health. These chemotypes have continued to attract increased research attention over the years; hence, numerous natural and synthetic chalcones have found with interesting anticancer activities through the inhibition of various molecular targets including ABCG2, BCRP, P-glycoprotein, 5α-reductase, Androgen Receptor (AR), Histone Deacetylases (HDAC), Sirtuin 1, proteasome, Vascular Endothelial Growth Factor (VEGF), Cathepsin-K, tubulin, CDC25B phosphatase, Topoisomerase, EBV, NF-κB, mTOR, BRAF, and Wnt/β-catenin. Moreover, the study of intrinsic mechanisms of action, particularly relating to specific cellular pathways and modes of engagement with molecular targets, may help medicinal chemists to develop more effective, selective, and cost-effective chalcone-based anticancer drugs. This review, therefore, sheds light on the effect of structural variations on the anticancer potency of chalcone hybrids reported in 2018-2019 alongside their mechanism of action, molecular targets, and potential impacts on effective cancer chemotherapy.

Mycoplasma hyorhinis (M. hyorhinis) lacks a cell wall and resists multiple antibiotics. We describe here the striking > 90% inhibitory effect of hemin, a natural inducer of the cytoprotective enzyme heme oxygenase‐1 (HO‐1), on M. hyorhinis replication in chronically infected LNCaP prostate cancer cells. The role of HO‐1 in interrupting M. hyorhinis replication was confirmed by HO‐1‐specific siRNA suppression of hemin‐induced HO‐1 protein expression, which increased intracellular M. hyorhinis DNA levels in LNCaP cells. Proteomic analysis and transmission electron microscopy of hemin‐treated cells confirmed the complete absence of M. hyorhinis proteins and intact microorganisms, respectively, strongly supporting these findings. Our study is the first to our knowledge suggesting therapeutic potential for activated HO‐1 in cellular innate responses against mycoplasma infection., This study demonstrates inhibition of antibiotic‐resistant mycoplasma M. hyorhinis replication in human prostate cancer cells by the inducible cytoprotective enzyme heme oxygenase‐1 (HO‐1). Hemin induces mRNA and protein for this ubiquitous HO‐1 component of innate cellular immunity. Hemin is the active component of an FDA‐approved drug for another indication and could potentially provide a therapeutic modality for treating mycoplasma infection.

Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (MASTL; Microtubule-associated serine/threonine-protein kinase-like) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown. Based on a comprehensive investigation involving PC patient samples, murine models of PC progression (Kras;PdxCre-KC and Kras;p53;PdxCre-KPC), and loss and gain of function studies, we report a previously undescribed critical role of MASTL in promoting cancer malignancy and therapy resistance. Mechanistically, MASTL promotes PC by modulating the epidermal growth factor receptor (EGFR) protein stability and, thereupon, kinase signaling. We further demonstrate that combinatorial therapy targeting MASTL promotes the efficacy of the cell-killing effects of Gemcitabine using both genetic and pharmacological inhibitions. Taken together, this study identifies a key role of MASTL in promoting PC progression and its utility as a novel target in promoting sensitivity to the anti-pancreatic cancer therapies.

The mycotoxin patulin is primarily produced as a secondary metabolite by numerous fungal species and predominantly by Aspergillus, Byssochlamys, and Penicillium species. It is generally associated with fungal infected food materials. Penicillium expansum is considered the only fungal species liable for patulin contamination in pome fruits, especially in apples and apple-based products. This toxin in food poses serious health concerns and economic threat, which has aroused the need to adopt effective detection and mitigation strategies. Understanding its origin sources and biosynthetic mechanism stands essential for efficiently designing a management strategy against this fungal contamination. This review aims to present an updated outline of the sources of patulin occurrence in different foods and their biosynthetic mechanisms. It further provides information regarding the detrimental effects of patulin on human and agriculture as well as its effective detection, management, and control strategies.

A number of studies have examined the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) on intestinal inflammation driven by immune cells, while little information is currently available about its impact on inflammation caused by intestinal epithelial cell (IEC) defects. Mice lacking IEC-specific Rab11a a recycling endosome small GTPase resulted in increased epithelial cell production of inflammatory cytokines, notably IL-6 and early onset of enteritis. To determine whether vitamin D supplementation may benefit hosts with epithelial cell-originated mucosal inflammation, we evaluated in vivo effects of injected 1,25(OH)2 D3 or dietary supplement of a high dose of vitamin D on the gut phenotypes of IEC-specific Rab11a knockout mice (Rab11aΔIEC ). 1,25(OH)2 D3 administered at 25 ng, two doses per mouse, by intraperitoneal injection, reduced inflammatory cytokine production in knockout mice compared to vehicle-injected mice. Remarkably, feeding mice with dietary vitamin D supplementation at 20,000 IU/kg spanning fetal and postnatal developmental stages led to improved bodyweights, reduced immune cell infiltration, and decreased inflammatory cytokines. We found that these vitamin D effects were accompanied by decreased NF-κB (p65) in the knockout intestinal epithelia, reduced tissue-resident macrophages, and partial restoration of epithelial morphology. Our study suggests that dietary vitamin D supplementation may prevent and limit intestinal inflammation in hosts with high susceptibility to chronic inflammation.

Background: The use of cannabis is common among athletes and the US population at large. Cannabinoids are currently being evaluated as alternatives to opioid medications for chronic pain management. However, the effects of recreational and/or medical use of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on musculoskeletal injury and healing remain largely unknown. Hypothesis/Purpose: The purpose of this study was to evaluate the biomechanical effects of CBD and THC on tendon-to-tendon healing in a rat Achilles tendon repair model. The hypothesis was that rats administered CBD would demonstrate decreased tensile load to failure of surgically repaired Achilles tendons compared with the THC and control groups. Study Design: Controlled laboratory study. Methods: A total of 33 Sprague Dawley rats underwent Achilles tendon surgical transection and repair and were randomized to receive subcutaneous injection of THC, CBD, or vehicle once daily starting on the day of surgery and for 5 total days. After sacrifice, biomechanical tensile load-displacement testing was performed to determine Achilles tendon load to failure and stiffness. Data were analyzed by 1-way analysis of variance. Results: The THC group demonstrated the highest median load to failure, 18.7 N (95% CI, 15.3-19.2 N); the CBD group had the second highest at 16.9 N (95% CI, 15.1-19.8 N), and the control group had the lowest at 14.4 N (95% CI, 12.1-18.3 N). Stiffness was highest in the THC group at 4.1 N/mm (95% CI, 2.7-5.1 N/mm) compared with 3.6 N/mm (95% CI, 2.9-4.1 N/mm) for the CBD group and 3.6 N/mm (95% CI, 2.8-4.3 N/mm) for the control group. No statistically significant differences for strength and stiffness were observed between the groups. Conclusion: In this pilot study using an animal tendon-to-tendon repair model, neither THC nor CBD resulted in altered biomechanical characteristics compared to control. Clinical Relevance: Cannabinoids do not appear to adversely affect Achilles tendon healing.

A 21-year-old human immunodeficiency virus-positive male patient presented with complaints of multiple hyperpigmented verrucous papules over his perianal area. He reported having unprotected anal and oral sex with multiple male partners. On examination, superficial ill-defined perianal erosions were present. A first void urine sample and clinician-collected rectal and oropharyngeal swabs were sent for the detection of Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma spp. Rectal swab tested positive for all the four pathogens. Oropharyngeal swab and urine samples tested positive for C. trachomatis. The patient was treated with doxycycline and moxifloxacin. This case underscores the importance of screening of men who have sex with men for possible coinfections with multiple sexually transmitted pathogens.

Despite estimates suggesting Leptospira spp. being endemic in Southeast Asia, evidence remains limited. Diagnostic accuracy evaluations based on Leptospira ELISA mainly rely on hospitalized and severe patients; therefore, studies measuring the pathogen burden may be inaccurate in the community. We evaluated the Panbio Leptospira ELISA IgM among 656 febrile outpatients attending primary care in Chiangrai, Thailand, and Hlaing Tha Yar, Yangon, Myanmar. ELISA demonstrated limited diagnostic accuracy for the detection of acute leptospiral infection using the manufacturer recommended cutoff, with a sensitivity of 71.4% and specificity of 36.4%, and an area under the receiver operator characteristic curve value of 0.65 (95% CI: 0.41–0.89), compared with our reference test, the PCR assay. ELISA also performed poorly as a screening tool for detecting recent exposure to Leptospira spp. compared with the “gold-standard” microscopic agglutination test, with a specificity of 42.7%. We conclude that the utility of the Leptospira IgM ELISA for both serodiagnosis and seroprevalence is limited in our setting.

Studies on genetic diversity could enhance taxonomic authentication and evolutionary relationship among the species of Ocimum. Therefore, diversity among 36 Ocimum accessions representing species from different regions of world were analyzed using Start Codon-Targeted Polymorphism (SCoT) and inter-simple sequences repeat (ISSR) marker. Marker systems used in this study was potentially targeted the different regions of the genome and included 18 SCoT and 15 ISSR primers, which showed successful amplification profile for Ocimum. Between these two, SCoT revealed the highest mean value of percentage of Polymorphism (84.6%), polymorphic information content (PIC, 0.65), and resolving power (Rp, 8.80), which were higher than ISSR. A total of 140 and 111 amplicons were obtained with SCoT and ISSR marker. The Mantel test indicted a significant correlation (r2 = 0.44) between ISSR and SCoT, which suggested a common genetical background among the accessions. The principal coordinate study showed the selection of different Ocimum genotypes by the cluster analysis. This study will help and support identification, genetic mapping, and molecular ecology to enhance the breeding program's efficiency for developing elite varieties to meet industrial demand globally. The present study is the first report of the genetic diversity, and relationship determination with SCoT-based molecular marker among Ocimum accessions.

Introduction: Multidrug-resistant Acinetobacter baumannii is galloping, posing threat to tackle, and leaving us with limited options of treatment. Methods: The purpose of this study is to find the genotypic association in drug-resistant A. baumannii isolated from different sterile body fluids. Matrix-assisted laser desorption/ionization–time of flight confirmed A. baumannii isolates were taken and minimum inhibitory concentration (MIC) was determined by VITEK-2 AST system. The presence of resistance nodulation–division (RND)-efflux pump genes AdeABC-RS was detected by multiplex polymerase chain reaction. Results: Of the total 40 A. baumannii, 32 (80%) were multidrug resistant though all isolates were susceptible to Tigecycline. Similarly, 26 (81.25%) isolates were positive for RND-efflux pump genes AdeABC-RS. Discussion: RND efflux pump AdeABC-RS system plays a significant role in emerging multi drug resistant A. baumannii. Mutation in AdeS gene deciphers the role of regulatory gene. Hence, antimicrobial stewardship should be strictly followed and efflux pump inhibiting substances should be vigorously searched to bring back the era of existing antibiotics.

Chryseobacterium species are widely distributed in the environment. They are rarely found in hospital settings causing nosocomial infections. Limited data is available regarding their epidemiology, clinical significance and antimicrobial susceptibility patterns. This study was aimed to identify different species of Chryseobacterium using matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) and to correlate clinically with antimicrobial susceptibility patterns in a tertiary care hospital in north India. We also performed phenotypic tests, which may be useful to differentiate this bacterium from other non-fermenters. A total of 20 isolates of Chryseobacterium spp. were identified over a period of 3 years. Chryseobacterium indologenes (18/20) was the most common species isolated followed by Chryseobacterium gleum (2/20) from various clinical samples. Antimicrobial susceptibility testing (AST) was performed. Susceptibility to rifampicin was observed at a maximum (75%) followed by piperacillin-tazobactum (45%). Susceptibility against imipenem, meropenem, cotrimoxazole and cefoperazone-sulbactum were observed approximately 33%. Amikacin, cefotaxime and ceftazidime showed least susceptibility results. Further clinical correlation was established.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.Lignes directrices sur la prise en charge de l’amylose héréditaire à transthyrétine, accompagnée de polyneuropathie, au Canada.L’amylose héréditaire à transthyrétine (ATTRh) est une maladie évolutive, causée par des mutations du gène de la transthyrétine (TTR), qui entraînent un dysfonctionnement plurisystémique. L’agrégation, le mauvais repliement et la fibrillisation pathogènes de la TTR aboutissent au dépôt de protéines amyloïdes dans plusieurs organes, et affectent souvent le système nerveux périphérique et le cœur. Les troubles neurologiques fréquents comprennent une polyneuropathie sensorimotrice (PN), une neuropathie autonome, une polyneuropathie des petites fibres et le syndrome du canal carpien. Chez bon nombre de patients, la maladie a connu une évolution importante en raison de la pose tardive du diagnostic, la PN-ATTRh ne faisant pas l’objet d’un diagnostic différentiel. Santé Canada a approuvé, depuis peu, deux nouveaux médicaments modificateurs de la PN-ATTRh et efficaces contre l’affection, soit l’inotersen et le patisiran. La pose précoce du diagnostic revêt une importance cruciale dans l’instauration, en temps opportun, de ces tout nouveaux traitements qui atténuent les troubles, améliorent la qualité de vie et prolongent la survie. Les auteurs, par l’élaboration de la nouvelle ligne directrice, espèrent sensibiliser la communauté médicale à la PN-ATTRh, et améliorer les résultats cliniques qui y sont associés, en formulant des recommandations sur le diagnostic et le traitement de la maladie au Canada ainsi que sur la surveillance de son évolution.

A process for preparation of a microgreen and fruit based beverage was optimized using spinach ( Spinacia oleracea ) microgreen, pomegranate ( Punica granatum ), pineapple ( Ananascomosus ) and sugar. The blended juice in different ratios was analysed for total soluble solids, viscosity, sedimentation, acidity, metal chelation activity, free radical scavenging activity and reducing power. The optimized beverage had, 17.26 mL 100 mL -1 spinach microgreen juice, 57.07 mL 100 mL -1 pomegranate juice, 1.01 g 100 g -1 sugar and 24.66 mL 100 mL -1 pineapple juice. The product was high in nutrients, particularly protein, minerals (sodium, potassium and iron), and vitamins (vitamin C), and bioactive compounds (total phenols and total carotenoids) and had high antioxidant activity (metal chelation activity, free radical scavenging activity and reducing power). The antioxidants and bioactive compounds present in juice were designed to help reduce oxidative stress during inflammatory cases such as arthritis.

Stress intervenes in the brain’s capability to encode and regain information from a person, it alters the biochemical parameters in specific regions of the brain can cause long-term damage to various parts of brain. The present investigations aid in understanding the effect of the Prunus amygdalus nut extract on CUS induced memory deficits in rats. The methanolic extract with an antioxidant potential (~ 60%) and was selected for in vivo analysis. CUS was induced in rats using different stress paradigms for 10 days. On day 11 and 12, acquisition trials for memory evaluation were performed using Morris Water Maze. On day 13 and 10 days later on, i.e. day 23, short-term and long-term memory retrievals trials were evaluated, respectively. Treatment groups were given test methanolic extract an hour before the subjection of CUS. Biochemical estimations and histopathological studies were carried out using brain tissue homogenate and brain tissue section, respectively. CUS altered the Transfer Latency time in both acquisition and retrieval trials, indicating memory impairment, which was reduced significantly in extract-treated groups. Administration of P. amygdalus nut methanolic extract protected the rat brains against CUS-induced neuroinflammatory changes. The observed beneficial effects could be attributed to the antioxidant potential of P. amygdalus.

SIRT5 is a member of the sirtuin family of NAD(+)-dependent protein lysine deacylases implicated in a variety of physiological processes. SIRT5 removes negatively charged malonyl, succinyl, and glutaryl groups from lysine residues and thereby regulates multiple enzymes involved in cellular metabolism and other biological processes. SIRT5 is overexpressed in human breast cancers and other malignancies, but little is known about the therapeutic potential of SIRT5 inhibition for treating cancer. Here we report that genetic SIRT5 disruption in breast cancer cell lines and mouse models caused increased succinylation of IDH2 and other metabolic enzymes, increased oxidative stress, and impaired transformation and tumorigenesis. We, therefore, developed potent, selective, and cell-permeable small-molecule SIRT5 inhibitors. SIRT5 inhibition suppressed the transformed properties of cultured breast cancer cells and significantly reduced mammary tumor growth in vivo, in both genetically engineered and xenotransplant mouse models. Considering that Sirt5 knockout mice are generally normal, with only mild phenotypes observed, these data establish SIRT5 as a promising target for treating breast cancer. The new SIRT5 inhibitors provide useful probes for future investigations of SIRT5 and an avenue for targeting SIRT5 as a therapeutic strategy.

Банківська система є основою фінансової структури країни та основою її економічного зростання. Авторами зазначено, що оцінювання результативності функціонування банківської системи дозволяє своєчасно визначити відхилення від таргетованих значень економічного розвитку країни. При цьому в сучасних глобалізаційних умовах необхідним є розроблення та застосування інноваційних підходів оцінювання фінансової ефективності банківського сектору. У статті наголошено, що банківська система виступає детермінантою монетарної політики країни. З огляду на це, необхідним є забезпечення постійного контролю ефективності його функціонування. Головною метою дослідження є оцінювання фінансової результативності функціонування банківського сектору Саудівської Аравії з використанням інноваційних підходів. Об’єктом дослідження є банк умовно названий «XYZ». Для досягнення поставленої мети застосовано інноваційну модель CAMEL, яка є широко розповсюдженим підходом оцінювання фінансових результатів діяльності банківського сектору за критеріями достатності капіталу, якості активів, ефективності управління, якості доходів та ліквідності. Практичну реалізацію дослідження здійснено з використанням пакету програмного забезпечення SPSS Statistics. Емпіричне дослідження проведено за допомогою методу множинної лінійної регресії. Вихідні дані для дослідження сформовано за 2009-2018 роки. За результатами дослідження встановлено фактори моделі CAMEL, які мають неоднозначний вплив на фінансові результати діяльності банку XYZ. Зокрема, достатність капіталу та якість активів позитивно впливають на фінансову результативність банку. Авторами зазначено, що ефективність менеджменту в банку має статистично значущий вплив на його прибутковість, а змінна «якість доходів» має негативний вплив. Отримані результати свідчать про негативне співвідношення між якістю активів та рентабельністю інвестицій. На основі проведеного дослідження, авторами визначено, що банки з вищим операційним прибутком та ефективнішою системою управління ліквідністю мають вищу прибутковість. Враховуючі результати дослідження у статті запропоновано напрями підвищення ефективності діяльності банку XYZ, а саме: диверсифікація джерел доходів; підвищення ефективності управління; впровадження інноваційних методів оцінювання фінансових результатів діяльності банку. A robust financial structure is considered essential for the swift development and growth and of an economic system. The banking structure is a vital constituent of the financial structure of a nation. The banking system performance assessment is an influential determinant and indicator of the economy's financial strength. Financial Innovation approaches resulting from new technology helps in better estimation of Financial Performances of the banking sector. Banks need to be more closely and accurately watched as they play the role of facilitator of monetary policy of the economy. The prime objective is to examine the financial performance of Saudi Arabia's banking sector through Innovative approaches. With this view, a case study of XYZ Bank has been undertaken. For financial performance evaluation, the CAMEL model has been applied as one of the innovative approaches. This tool is a widely accepted criterion in the field of financial performance evaluation of the banking sector. CAMEL is a ratiosupported mechanism that evaluates bank performance through capital adequacy, quality of assets, management efficiency, quality of earnings, and liquidity. For analyzing the CAMEL model, the various ratios of the model in terms of proxy ratios are given below: For the analysis, nine-year data from 2009 to 2018 has been analyzed using a multiple linear regression model using the SPSS package. The study observed that this innovative approach, i.e., CAMEL specific factors, has mixed influence on the financial performance of XYZ Bank. Capital adequacy and asset quality have a positive effect on bank performance. Moreover, the study also highlights that management efficiency insignificantly affects the profitability of the bank. Moreover, earning quality also signifies a negative influence on profitability. The correlation between asset quality and ROA is negative. It is inferred that those banks with more operating profits and better liquidity management could report high profits. The study further advocates that XYZ Bank must improve its earning quality and management efficiency to come at the same level with the banks having good financial performance and should use innovative methods to estimate financial performance from time to time.

Cyclooxygenase-2 (COX-2) is an inducible enzyme which triggers the biosynthesis of prostaglandins. COX-2 is activated in response to inflammatory stimuli and is one of the major molecules that is involved in the development and progression of colorectal cancer (CRC). Consistent with such a conceptual framework, it has been shown that COX-2 inhibitors prevent the carcinogenesis of CRC and aid in the treatment of sporadic or familial cases of CRC as shown by an overall increase in the survival rate. However, prolonged use of these inhibitors is associated with increase risk of development of cardiovascular complications, implying that further research is required to identify COX-2 inhibitors that are associated with lower risks of such complications.

Intensive crop production and extensive use of harmful synthetic chemical pesticides create numerous socio-economic problems worldwide. Therefore, sustainable solutions are needed for insect pest control, such as biological control agents. The fungal insect pathogen Beauveria bassiana has shown considerable potential as a biological control agent against a broad range of insects. The insight into the virulence mechanism of B. bassiana is essential to show the robustness of its use. B. bassiana has several determinants of virulence, including the production of cuticle-degrading enzymes (CDEs), such as proteases, chitinases, and lipases. CDEs are essential in the infection process as they hydrolyze the significant components of the insect's cuticle. Moreover, B. bassiana has evolved effective antioxidant mechanisms that include enzyme families that act as reactive oxygen species (ROS) scavengers, e.g., superoxide dismutases, catalases, peroxidases, and thioredoxins. In B. bassiana, the number of CDEs and antioxidant enzymes are characterized in recent years. These enzymes are believed to be crucial player of evolutionary process in this organism and their role in various mechanism of biological control. Recent discoveries have significantly increased our potential understanding on several potentially wanted unknown mechanisms of B. bassiana infection. This review focuses on the progress detailed in the studies of these enzymes and provides an overview of enzymatic activities and their contributions to virulence.

Rice is sensitive to heat stress at gametogenesis and anthesis stages. For sustaining rice yields under the predicted threat of reproductive stage heat stress (RSHS), identification of tolerant donors as well as mapping of genes governing tolerance is crucial. Recently a NERICA (NEwRIce for AfriCA) rice genotype, NL44 has been reported tolerant to RSHS. The present study aims to survey a recombinant inbred line (RIL) population developed from the cross, Pusa Basmati 1 (PB1)/NL44 using markers linked to 54 RSHS quantitative trait loci (QTLs) through phenotypic and genotypic characterization. When exposed to RSHS, the susceptible parent PB1 and several RILs showed significant reduction for spikelet fertility and grain yield plant−1 relative to NL44. Both these traits and the estimated stress tolerance index (STI) showed a quantitative pattern of inheritance. Out of the 116 SSR markers surveyed, 31 markers were polymorphic between PB1 and NL44. No discernible associations could be found through a preliminary bulked segregant analysis with these markers. A subsequent single marker analysis revealed five minor QTLs, four for spikelet fertility under heat stress and two for STI-spikelet fertility, of which one QTL was mapped for both the traits. These QTLs, however, could explain a very low level of total phenotypic variation. Additionally, the cumulative additive effect of these QTLs could account only for a possible 30% of the contrast between PB1 and NL44. Thus, the study clearly establishes that NL44 has novel genomic regions for RSHS tolerance.

Objectives: In this study, silver nanoparticles (AgNPs) were synthesized using healthy plant parts like fruits, stem and leaves of Ficus racemosa. Methods: The collected plant samples were processed by cleaning, drying and grinding. Bioactive compounds were extracted by using Soxhlet extraction method. The 10mg of plant extract was added to 1mM AgNO3 solution and incubated at 80°C for 3min. The UV-Vis spectroscopy was used for characterization of produced AgNPs. The synthesis process was optimized for pH (3 to 9), plant extracts conc. (0.5, 1, 2, 4 and 8mg/2ml), incubation temp. (50°C, 60°C upto 100°C) and silver salt conc. (0.125, 0.25, 0.50, 1.0 and 2mM). Finally the antimicrobial and seed germination ability of synthesized AgNPs was determined. Results: The λmax values were found to be 464.50nm, 422nm and 489nm for fruits, stem and leaves respectively. FTIR spectra of control and test were determined which showed the different functional groups in the synthesized AgNPs. The optimum pH (9, 8 and 8), plant extracts conc. (8, 4 and 8mg), incubation temp. (80°C, 90°C and 100°C) and silver salt conc. (2mM, 1.5mM and 2mM) for fruit, stem and leaves AgNPs were determined. The selective NPs showed notable antibacterial activity against Gram positive bacteria like S. equorum and B. subtilis and significant effect on wheat (Triticum aestivum L.) seed germination. Conclusion: The green synthesis process was found to be time saving and effective approach for the synthesis of the AgNPs from different plant parts. Produced NPs have potential applications in therapeutics and agriculture.

Introduction The soft tissue envelope around the knee can have an impact on the ease of performing surgery such as total knee replacement (TKR). BMI is often used in planning theatre time but may be a poor indicator of the soft tissue around the knee due to varying distribution of adipose tissue. Radiological images directly show the soft tissue. We therefore aim to develop a method of quantifying the soft tissue envelope around the knee using radiographs. Method Plain weight-bearing radiographs were used to measure the total knee (soft tissue and bony) width at the level of the epicondyles of the knee and the bony epicondylar width of the femur. The ratio of the two widths was defined as the Soft Tissue Radiological Knee (SToRK) Index. The validity of the index as a true measure of soft tissue envelope was assessed using cross sectional areas on axial MRI cuts at the level of the epicondyles. The inter-observer reliability was assessed using the intra-class correlation coefficient. SToRK Index values were correlated with patients’ BMI, gender and operative time. Results The results show there is a close correlation between the ratio of cross sectional area of MRI axial cuts at the level of epicondyles and the ratio of linear widths measured on plain radiographs, validating the SToRK Index as a measure of soft tissue envelope. There was also good to excellent inter-rater reliability of measurements of these widths. There was a close correlation between BMI and SToRK Index with differences between men and women. Discussion We believe the SToRK Index is a validated method of quantifying soft tissue distribution around the knee and gives surgeons a better descriptor of the knee envelope than BMI. It is easy to use, needs simple investigations and is reproducible.

Synthesis of metallic nanoparticles via green approach holds great potential in diverse fields of biotechnology and medicine with special mention to silver nanoparticles (AgNPs) which undoubtedly display antimicrobial, radical scavenging, and dye degradation properties. Currently, there is a need to explore more cost-effective and efficient methods to synthesize AgNPs. In this study, we have synthesized biogenic AgNPs using an aqueous extract of a flowering plant of the legume family, Fabaceae, subfamily Caesalpiniaceae, Cassia fistula, which is also well known for its medicinal values. Spectroscopically and physicochemically characterized AgNPs were evaluated for their cytocompatibility, antimicrobial effects, antioxidant and catalytic activity to establish their potential for various biomedical applications. DLS studies revealed their size ~ 237 nm with the surface charge of ~ − 30 mV. The results of the zone of inhibition and MIC assays showed the superiority of the activity of these particles over the pod extract. Catalytic reduction of toxic p-nitrophenol to benign p-aminophenol as well as degradation of hazardous industrial dyes (methyl orange and methylene blue) advocated their potential as environmental toxicant eradicators. Besides, these biogenic AgNPs displayed profound antibiofilm effects in static microtiter plates. Altogether, the results of various bioassays using these biogenic nanoparticles demonstrate their immense potential as antimicrobial, antioxidant, and antibiofilm agents.

Targeting mitotic kinases is an emerging anticancer approach with promising preclinical outcomes. Microtubule‐associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl), is an important mitotic kinase that regulates mitotic progression of normal or transformed cells by blocking the activity of tumor suppressor protein phosphatase 2A (PP2A). MASTL upregulation has now been detected in multiple cancer types and associated with aggressive clinicopathological features. Apart, an aberrant MASTL activity has been implicated in oncogenic transformation through the development of chromosomal instability and alteration of key oncogenic signaling pathways. In this regard, recent publications have revealed potential role of MASTL in the regulation of AKT/mTOR and Wnt/β‐catenin signaling pathways, which may be independent of its regulation of PP2A‐B55 (PP2A holoenzyme containing a B55‐family regulatory subunit). Taken together, MASTL kinase has emerged as a novel target for cancer therapeutics, and hence development of small molecule inhibitors of MASTL may significantly improve the clinical outcomes of cancer patients. In this article, we review the role of MASTL in cancer progression and the current gaps in this knowledge. We also discuss potential efficacy of MASTL expression for cancer diagnosis and therapy., In this article, we review the role of MASTL in cancer progression and the current gaps in this knowledge. We also discuss potential efficacy of MASTL expression for cancer diagnosis and therapy.

Background There are ongoing clinical trials exploring the efficacy of dopamine receptor D2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy. Methods The Cancer Genome Atlas glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and epidermal growth factor receptor (EGFR) expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient-derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201. Results Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD2 mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, variant (v)III, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (0.037). Conclusions High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.

Diabetic kidney disease (DKD) is a major complication of diabetes and the leading cause of end-stage renal failure. Epigenetics has been associated with metabolic memory in which prior periods of hyperglycemia enhance the future risk of developing DKD despite subsequent glycemic control. To understand the mechanistic role of such epigenetic memory in human DKD and to identify new therapeutic targets, we profiled gene expression, DNA methylation, and chromatin accessibility in kidney proximal tubule epithelial cells (PTECs) derived from subjects with and without type 2 diabetes (T2D). T2D-PTECs displayed persistent gene expression and epigenetic changes with and without transforming growth factor-β1 treatment, even after culturing in vitro under similar conditions as nondiabetic PTECs, signified by deregulation of fibrotic and transport-associated genes (TAGs). Motif analysis of differential DNA methylation and chromatin accessibility regions associated with genes differentially regulated in T2D revealed enrichment for SMAD3, HNF4A, and CTCF transcription factor binding sites. Furthermore, the downregulation of several TAGs in T2D (including CLDN10, CLDN14, CLDN16, SLC16A2, and SLC16A5) was associated with promoter hypermethylation, decreased chromatin accessibility, and reduced enrichment of HNF4A, histone H3-lysine-27-acetylation, and CTCF. Together, these integrative analyses reveal epigenetic memory underlying the deregulation of key target genes in T2D-PTECs that may contribute to sustained renal dysfunction in DKD.

The unexpected seroconversion of sentinel mice in our facility to murine T lymphotrophic virus (MTLV) positivity led to our identification of a novel murine astrovirus that we designated murine astrovirus 2 (MuAstV-2). During our investigation, MuAstV-2 was found to be a contaminant of the T helper cell line (D10. G4.1) that was used to generate the MTLV antigen that we included in the multiplex fluorometric immunoassay (MFIA) that we used for sentinel screening. We eventually determined that cross-reactivity with the astrovirus generated a positive result in the MTLV assay. A confirmatory immunofluorometric assay (IFA) using the same MTLV-infected cell line yielded a similar result. However, the use of antigen prepared from MTLV-infected neonatal mouse thymus did not reproduce a positive result, leading us to suspect that the seroreactivity we had observed was not due to infection with MTLV. A mouse antibody production test showed that mice inoculated with naïve D10. G4.1 cells and their contact sentinels tested positive for MTLV using cell-line generated antigen, but tested negative in assays using MTLV antigen produced in mice. Metagenomic analysis was subsequently used to identify MuAstV-2 in feces from 2 sentinel mice that had recently seroconverted to MTLV. Two closely related astrovirus sequences (99.6% capsid identity) were obtained and shared 95% capsid amino acid identity with the MuAstV-2 virus sequenced from the D10. G4.1 cell line. These viruses are highly divergent from previously identified murine astroviruses, displaying Prkdcem26Cd52Il2rgem26Cd22/NjuCrl (NCG) mice, which have significantly impaired adaptive and innate immune systems. Neither immunocompetent nor immunodeficient mice showed any astrovirus-associated pathology. MuAstV-2 may provide a valuable model for the study of specific aspects of astrovirus pathogenesis and virus-host interactions.

Objectives: To evaluate the antibiofilm potential of Terminalia arjuna and Ipomea carnea plant extract against potent biofilm forming UTI pathogens. Methods/Statistical analysis: In this study, previously isolated and characterized three UTI pathogens viz. Escherichia coli, Pseudomonas aeruginosa and Staphylococcus equorum were used to evaluate antibiofilm potential of selected plants. Soxhlet apparatus was used with a solvent methanol for the extraction process. For the evaluation of antibiofilm activity of different concentrations (2, 4, 6, 8 and 10 mg/ml) of plant extract in 3% DMSO Crystal violet assay was used. Findings: The methanolic bark extract of T. arjuna showed maximum activity up to 89.84% at 10mg/ml. against S. equorum while leaves extract of I. carnea gives maximum antibiofilm activity up to 67.53% at 2mg/ml against E. coli. The result shows that the investigated plants might be helpful in the development of potent herbal drugs to treat UTI. Keywords: T. arjuna; I. carnea; E. coli; P. aeruginosa; S. equorum; Soxhletextraction; Crystal violet assay

Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance., Acquired resistance to cancer therapies reflects the ability of cancers to adapt to therapy-imposed selective pressures. Here, the authors elucidate the dynamics of developing resistance to ALK inhibitors in an ALK+ lung cancer cell line showing that resistance originates from drug-specific tolerant cancer cells and it develops as a gradual adaptation.

Breakthroughs in our understanding of the complex interplay between cellular nanoenvironment and biomolecular signalling pathways are facilitating development of targeted osteogenic platforms. As critical biomolecules for osteogenesis, growth factors stimulate osteogenesis by activating key genes and transcription factors. The first half of this review presents emerging interconnectedness and recent discoveries of osteogenic signalling pathways initiating from growth factors for example, bone morphogenetic protein 2 (BMP-2). To complement this, the second half of review proposes a number of strategies to induce osteogenesis which include metallic, organic implants, nanotopological environments as well as growth factor immobilization techniques. The drawbacks of traditional osteogenic implants and how these have been overcome by biomedical engineers in the recent years without producing side-effects have also been summarized.

Microarray is among the recent development of molecular biology that has been applied to various fields of biological research. It is a high-throughput technology perfected over the years. Briefly, microarray can be defined as a lab-on-a-chip technique that collectively contains spots of thousands of biological material like nucleic acid or protein on a silicon or glass chip. These spots with which microarray are produced can be customized according to the experiment’s requirements and primarily depend on the available sequence of the biological material of the organism. The basic principle that the microarray is based on is similar to the hybridization technique; therefore, a test sample containing the appropriate biomaterial is prepared and is hybridized with the microarray. The hybridization with complement biomaterial generates signals that can be read and analyzed to assess the expression of genes or proteins in the test samples. In this chapter, we discuss the principle, origin, and application of microarrays to decipher host-pathogen interactions.

Immunotherapy with the success of checkpoint blockade brings hope for cancer treatment with enduring or complete responses in various types of advanced malignancies, however, it has not benefited a number of so called “cold tumors”, such as glioblastoma multiforme (GBM), the most common and aggressive adult brain cancer. GBM is invariably lethal with a median survival of less than 15 months and characterized by a highly immunosuppressive tumor microenvironment, which desires new means of GBM immune-reactivation. Tissue-resident memory CD8+ T (TRM) cells are non-recirculating memory T cell subpopulation that resides permanently in peripheral tissues. TRM cells provide long-lived protective immunity against not only local pathogen infection but also tumor development through immediate effector function and recruitment of circulating immune cells upon antigen re-exposure. In this study, we found that memory T cells specific to some common human viruses that have infected almost everybody exist in clinical GBM specimens and can be activated by viral peptides, which are MHC I restricted CD8+ T cell epitopes derived from those viruses. In orthotopic GBM immunocompetent mouse models, we detected abundant virus specific TRM cells in the tumor microenvironment of GBMs intracranially established in mice that were previously exposed to the virus. Excitingly, intratumoral injection of viral peptides stimulated the reactivation of TRM cells, indicated by secretion of immuno-stimulatory cytokines, and demonstrated significant anti-tumor efficacy. This study provides proof of principle for TRM cell-based GBM therapy, which is a novel therapeutic paradigm with the translational potential for this deadly malignancy.

Precision medicine offers remarkable potential for the treatment of cancer, but is largely focused on tumors that harbor actionable mutations. Gene expression signatures can expand the scope of precision medicine by predicting response to traditional (cytotoxic) chemotherapy agents without relying on changes in mutational status. We present a novel signature extraction method, inspired by the principle of convergent evolution, which states that tumors with disparate genetic backgrounds may evolve similar phenotypes independently. This evolutionary-informed method can be utilized to produce signatures predictive of response to over 200 chemotherapeutic drugs found in the Genomics of Drug Sensitivity in Cancer Database. Here, we demonstrate its use by extracting the Cisplatin Response Signature, CisSig, for use in predicting a common trait (sensitivity to cisplatin) across disparate tumor subtypes (epithelial-origin tumors). CisSig is predictive of cisplatin response within the cell lines and clinical trends in independent datasets of tumor samples. Finally, we demonstrate preliminary validation of CisSig for use in muscle-invasive cancer, predicting overall survival in patients who undergo cisplatin-containing chemotherapy. This novel methodology can be used to produce robust signatures for the prediction of traditional chemotherapeutic response, dramatically increasing the reach of personalized medicine in cancer.Translational RelevanceMost precision medicine research focuses on using targeted drugs on patients with known driver mutations, yet the majority of patients don’t have actionable mutations. Using a novel signature extraction method, we produce the Cisplatin Response Signature (CisSig) to predict how well patients with epithelial-origin tumors will respond to cisplatin, a common cytotoxic chemotherapy. We show that expression of CisSig is correlated to clinical trends of cisplatin use in treatment guidelines using independent tumor databases. Then, we look at preliminary validation of CisSig for use in patients with muscle-invasive bladder cancer. Using two independent cohorts of pre-treatment tumor samples, we show that a CisSig-trained model is predictive of overall survival in patients who did receive cisplatin, but this signal is lost in patients who did not receive cisplatin–indicating that the model is predictive of therapeutic response, not simply prognosis.