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Nature Communications Jun 2020Metastatic melanoma is challenging to manage. Although targeted- and immune therapies have extended survival, most patients experience therapy resistance. The... (Review)
Review
Metastatic melanoma is challenging to manage. Although targeted- and immune therapies have extended survival, most patients experience therapy resistance. The adaptability of melanoma cells in nutrient- and therapeutically-challenged environments distinguishes melanoma as an ideal model for investigating therapy resistance. In this review, we discuss the current available repertoire of melanoma models including two- and three-dimensional tissue cultures, organoids, genetically engineered mice and patient-derived xenograft. In particular, we highlight how each system recapitulates different features of melanoma adaptability and can be used to better understand melanoma development, progression and therapy resistance.
Topics: Animals; Antinematodal Agents; Biomarkers, Tumor; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Humans; Melanoma; Mice; Mice, Transgenic; Organoids; Skin; Skin Neoplasms; Spheroids, Cellular; Xenograft Model Antitumor Assays
PubMed: 32504051
DOI: 10.1038/s41467-020-15546-9 -
The Journal of Antimicrobial... Jul 2023Invasive candidiasis (IC) is a serious infection caused by several Candida species, and the most common fungal disease in hospitals in high-income countries. Despite... (Review)
Review
Invasive candidiasis (IC) is a serious infection caused by several Candida species, and the most common fungal disease in hospitals in high-income countries. Despite overall improvements in health systems and ICU care in the last few decades, as well as the development of different antifungals and microbiological techniques, mortality rates in IC have not substantially improved. The aim of this review is to summarize the main issues underlying the management of adults affected by IC, focusing on specific forms of the infection: IC developed by ICU patients, IC observed in haematological patients, breakthrough candidaemia, sanctuary site candidiasis, intra-abdominal infections and other challenging infections. Several key challenges need to be tackled to improve the clinical management and outcomes of IC patients. These include the lack of global epidemiological data for IC, the limitations of the diagnostic tests and risk scoring tools currently available, the absence of standardized effectiveness outcomes and long-term data for IC, the timing for the initiation of antifungal therapy and the limited recommendations on the optimal step-down therapy from echinocandins to azoles or the total duration of therapy. The availability of new compounds may overcome some of the challenges identified and increase the existing options for management of chronic Candida infections and ambulant patient treatments. However, early identification of patients that require antifungal therapy and treatment of sanctuary site infections remain a challenge and will require further innovations.
Topics: Humans; Adult; Antifungal Agents; Echinocandins; Candidiasis, Invasive; Candidemia
PubMed: 37220664
DOI: 10.1093/jac/dkad139 -
Archives of Pathology & Laboratory... Jan 2022Because granulomas are represented in almost every disease category, the number of clinically and pathologically important granulomatous pulmonary diseases is large.... (Review)
Review
CONTEXT.—
Because granulomas are represented in almost every disease category, the number of clinically and pathologically important granulomatous pulmonary diseases is large. Their diagnosis by pathologists is particularly challenging because of their nonspecificity. A specific diagnosis can be achieved only when a granuloma-inciting agent(s) (eg, acid-fast bacilli, fungi, foreign bodies, etc) are identified microscopically or by culture; this does not occur in most cases. Furthermore, a specific diagnosis cannot be reached in a high percentage of cases. Although sarcoidosis and infectious diseases account for approximately half of pulmonary granulomatous diseases worldwide, there is significant geographic variation in their prevalence.
OBJECTIVES.—
To present updated information to serve as a guide to pathologic diagnosis of pulmonary granulomatous diseases, to address some commonly held misconceptions and to stress the importance of multidisciplinary coordination. Presentation of basic aspects of granulomas is followed by discussion of specific disease entities, such as tuberculous and nontuberculous Mycobacterial infections, fungal, bacterial, and parasitic infections, sarcoidosis, necrotizing sarcoid granulomatosis, berylliosis, hypersensitivity pneumonitis, hot tub lung, rheumatoid nodule, bronchocentric granulomatosis, aspirated, inhaled, and embolized foreign bodies, drug-induced granulomas, chronic granulomatous disease, common variable immunodeficiency, and granulomatous lesions associated with various types of cancer.
DATA SOURCES.—
Review of pertinent medical literature using the PubMed search engine and the author's practical experience.
CONCLUSIONS.—
Although the diagnosis of granulomatous lung diseases continues to present significant challenges to pathologists, the information presented in this review can be helpful in overcoming them. The importance of multidisciplinary coordination in cases where morphologic diagnosis is not possible cannot be overstated.
Topics: Alveolitis, Extrinsic Allergic; Granuloma; Humans; Lung; Lung Diseases; Sarcoidosis
PubMed: 33905479
DOI: 10.5858/arpa.2020-0543-RA -
Qatar Medical Journal 2019Sepsis, a medical emergency and life-threatening disorder, results from abnormal host response to infection that leads to acute organ dysfunction. Sepsis is a major...
Sepsis, a medical emergency and life-threatening disorder, results from abnormal host response to infection that leads to acute organ dysfunction. Sepsis is a major killer across all ages and countries and remains the most common cause of admission and death in the Intensive Care Unit (ICU). The true incidence remains elusive and estimates of the global burden of sepsis remain a wild guess. One study suggested over 19 million cases and 5 million sepsis-related deaths annually. Addressing the challenge, the World Health Assembly of the World Health Organisation (WHO) passed a resolution on better prevention, diagnosis, and management of sepsis. Despite thousands of articles and hundreds of trials, sepsis remains a major killer. The cornerstones of sepsis care remain early recognition, adoption of a systematic evidence-based bundle of care, and timely escalation to higher level of care. The bundle approach has been advocated since 2004 but underwent major modifications in subsequent years with more emphasis on the time-critical nature of sepsis and need to restore physiological variables within one hour of recognition. A shift from a three and six-hour bundle to one-hour bundle has been recommended. This single hour approach has been faced with an outcry and been challenged. Over several decades, the individual components of the sepsis bundle have not changed. Encountering a patient with suspected sepsis, one should measure lactate, obtain blood cultures, swiftly administer broad spectrum antimicrobials and fluids, and infuse vasopressors. A critical question arises: should we do this for all patients? Sepsis is not septic shock and guidelines did not make distinctive recommendations for each. Septic patients will present differently with some having more subtle signs and symptoms. Phenotypically, we do not know which patient with infection will develop a dysregulated host response and will succumb to sepsis and/or shock. The existing bundle lacks high quality evidence to support its recommendations and a blanket implementation for all patients with 'suspected' sepsis could be harmful. Indeed, a significant reduction of sepsis and septic shock in Australia and New Zealand was observed in a bundle-free region. Upon arrival in the ED, patients will be triaged. This is 'time zero'. Those with hypotension and hypoperfusion will be easily recognised and at most need to receive emergent care. Sepsis, per se, may not manifest clear cut signs and expertise to identify it is required. Those with non-specific symptoms may trigger an early warning scoring system and receive unnecessary antimicrobials and a large volume of intravenous (IV) fluids. Both therapies are not without significant side effects. Putting pressure on ED physicians to implement the 60-minute bundle without individualisation of care puts our patients at risk. Given the heterogenous nature and diverse pathobiological pathways, sepsis diagnosis can be challenging and both over and under-treatment can result. Established biomarkers such as procalcitonin and C-reactive protein lack specificity to rule out infection as the cause of inflammation. Currently, no laboratory test or biomarker helps predict which patients with infection or inflammation will develop organ dysfunction. A dire need for a specific sepsis biomarker exists. Modern molecular-based technologies are evolving and utilise polymerase chain reaction (PCR), nanotechnology, and microfluidics for point-of-care testing. Some devices identify causative microorganisms and their sensitivity in less than an hour. Catecholamines along with IV fluids are indicated to restore perfusion. However, inadvertent side effects may arise, especially at higher doses. Anti-adrenergic ß-blockers improve cardiac performance, enhance receptor responsiveness, and possess anti-inflammatory action. All are desirable in patients with septic shock. One randomised trial showed beneficial and protective effects of ß-blockers in septic shock. Rapidly acting titratable agents should be used in conjunction with appropriate hemodynamic monitoring and after adequate volume resuscitation. There is no consensus on target heart rate but an arbitrary cut off of 80-95 beats per minute is reasonable. Fluid resuscitation is the cornerstone of sepsis management. There is also compelling evidence that too much fluid is bad. Starch-based colloids should not be used in septic shock. Albumin is an alternative when large volumes are required but is not appropriate in traumatic brain injury. Balanced, less chloride and less acidic crystalloids are safer for the kidneys and are preferred over normal saline. Doses of IV fluids should be tailored to the patient's condition and a 30 ml/kg recommendation should be reviewed. Effective sepsis management requires adequate dosing of antimicrobials. Significant alteration of pharmacokinetics and pharmacodynamics is characteristic of septic shock. Accurate and effective dosing is challenging particularly in patients with multiple comorbidities and those receiving extracorporeal organ support. Underdosing results in treatment failure, whilst overdosing leads to toxicity and the risk of developing multi-drug resistant organisms. An individualised approach supported by therapeutic drug monitoring is suggested to ensure clinical efficacy. The search for a cure for sepsis is ongoing. A large prospective, randomised two-arm, parallel group study aims to recruit over 200 patients with septic shock across critical care units in Qatar. Evaluation of Hydrocortisone, Vitamin C, and Thiamine (HYVITS) examines the safety and efficacy of this triple therapy. Children are particularly vulnerable to sepsis. 1 in 6 children admitted with septic shock to ICU will die. As the majority of paediatric sepsis cases are community acquired, there is a strong need to raise awareness both for families and primary healthcare providers. Akin to adults, a bundle-approach to paediatric sepsis is strongly encouraged. National programs for paediatric sepsis have been established. The Qatar paediatric multidisciplinary sepsis program was established under the umbrella of the adult programme in 2017. A structured and standardised approach to sepsis across all neonate and paediatric facilities has been developed and implemented. Improvement in timely sepsis recognition and administration of antimicrobials within the golden hour has been observed. The program aims to achieve a 95% compliance to the paediatric sepsis bundle by the end of 2019. A screening tool and order set have been put in place and are presented in this special issue of Qatar Medical Journal. Pregnancy and childbirth are risk factors for sepsis. Multi-organ failure and death can result from puerperal sepsis. Sepsis is the direct and leading cause of maternal mortality in the UK. Attention to maternal sepsis with a tailored approach is encouraged. The Qatar National Sepsis Program developed a sepsis care pathway for pregnant women and during their early post-partum period. A broader, national -or better yet- a global approach to further sepsis management and outcome should be considered. There are a number of significant challenges to address. One such challenge is the inconsistency of the operational definition and diagnostic approaches for sepsis including coding and documentation. Significant deficiencies in healthcare systems have been highlighted by sepsis. This is most obvious in medium- and low-income countries. A major limitation to effective sepsis management is inadequate medical staffing and poor knowledge and awareness of sepsis. Both have a negative impact on sepsis outcome. Poor medical facilities in many countries pose significant challenges to sepsis care. Lack of critical care capacity - a global phenomenon - has been linked to poor outcome of sepsis cases and septic shock. This could be attributed to provision of suboptimal critical care, monitoring and critical interventions outside of the ICU. ICU availability is subject to inconsistency and inequity. Lack of adequate surgical capacity to accomplish timely source control adversely affects sepsis management. This, unfortunately, in medium- and low-income countries, is accompanied by inadequate medical supplies, diagnostic capacity, and manpower which increases sepsis mortality and morbidity. Antimicrobials are critical for sepsis care. A global concern is the development of multi-drug resistant organisms and the lack of novel antimicrobials and this adds pressure on those caring for septic patients. Effective antimicrobials should be utilised to eradicate infections. Misuse, inadequacy, inferior agents, and lack of timely access to effective and affordable agents significantly hinders patient's recovery from sepsis. Optimum sepsis outcome mandates attention to acute sepsis complications (e.g. acute renal or respiratory failure) as well as addressing post-discharge complications and disability. These challenging issues remain poorly studied or addressed. Sepsis and septic shock are major global health concerns. Progress has been achieved in understanding this life-threatening syndrome at a biological, metabolic, and cellular level. Efforts should be coordinated to improve sepsis care. Better and more accurate diagnostics are needed and governments are encouraged to invest in sepsis research and care. More integrated, inclusive, and focused research is desperately needed. Public education and increased awareness among primary healthcare providers are also critical to improve sepsis outcome.
PubMed: 31763206
DOI: 10.5339/qmj.2019.qccc.4 -
Molecules (Basel, Switzerland) Dec 2020Taxol, which is also known as paclitaxel, is a chemotherapeutic agent widely used to treat different cancers. Since the discovery of its antitumoral activity, Taxol has... (Review)
Review
Taxol, which is also known as paclitaxel, is a chemotherapeutic agent widely used to treat different cancers. Since the discovery of its antitumoral activity, Taxol has been used to treat over one million patients, making it one of the most widely employed antitumoral drugs. Taxol was the first microtubule targeting agent described in the literature, with its main mechanism of action consisting of the disruption of microtubule dynamics, thus inducing mitotic arrest and cell death. However, secondary mechanisms for achieving apoptosis have also been demonstrated. Despite its wide use, Taxol has certain disadvantages. The main challenges facing Taxol are the need to find an environmentally sustainable production method based on the use of microorganisms, increase its bioavailability without exerting adverse effects on the health of patients and minimize the resistance presented by a high percentage of cells treated with paclitaxel. This review details, in a succinct manner, the main aspects of this important drug, from its discovery to the present day. We highlight the main challenges that must be faced in the coming years, in order to increase the effectiveness of Taxol as an anticancer agent.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Drug Resistance, Neoplasm; Humans; M Phase Cell Cycle Checkpoints; Microtubules; Neoplasms; Paclitaxel; Taxus
PubMed: 33348838
DOI: 10.3390/molecules25245986 -
Frontiers in Immunology 2021Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment...
Intestinal microbiota dysbiosis is an established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an attractive alternative UC treatment strategy, considering the potential adverse effects of synthetic drugs used to treat UC. Kaempferol (Kae) is an anti-inflammatory and antioxidant flavonoid derived from a variety of medicinal plants. In this study, we determined the efficacy and mechanism of action of Kae as an anti-UC agent in dextran sulfate sodium (DSS)-induced colitis mice. DSS challenge in a mouse model of UC led to weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by pretreatment with Kae. In addition, intestinal permeability was shown to improve using fluorescein isothiocyanate (FITC)-dextran administration. DSS-induced destruction of the intestinal barrier was also significantly prevented by Kae administration increases in the levels of ZO-1, occludin, and claudin-1. Furthermore, Kae pretreatment decreased the levels of , and and downregulated transcription of an array of inflammatory signaling molecules, while it increased mRNA expression. Notably, Kae reshaped the intestinal microbiome by elevating the to ratio; increasing the linear discriminant analysis scores of beneficial bacteria, such as and ; and reducing the richness of in DSS-challenged mice. There was also an evident shift in the profile of fecal metabolites in the Kae treatment group. Serum LPS levels and downstream TLR4-NF-κB signaling were downregulated by Kae supplementation. Moreover, fecal microbiota transplantation from Kae-treated mice to the DSS-induced mice confirmed the effects of Kae on modulating the gut microbiota to alleviate UC. Therefore, Kae may exert protective effects against colitis mice through regulating the gut microbiota and TLR4-related signaling pathways. This study demonstrates the anti-UC effects of Kae and its potential therapeutic mechanisms, and offers novel insights into the prevention of inflammatory diseases using natural products.
Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Colitis; Dextran Sulfate; Disease Models, Animal; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Intestinal Mucosa; Kaempferols; Lipopolysaccharides; Mice; NF-kappa B; Permeability; RNA, Ribosomal, 16S; Signal Transduction; Toll-Like Receptor 4
PubMed: 34367139
DOI: 10.3389/fimmu.2021.679897 -
Wellcome Open Research 2022Human infection (or challenge) studies involve the intentional administration of a pathogen (challenge agent) to volunteers. The selection, isolation, development and...
Human infection (or challenge) studies involve the intentional administration of a pathogen (challenge agent) to volunteers. The selection, isolation, development and production of the challenge agent is one of the first steps in developing a challenge study and critical for minimising the risk to volunteers. Regulatory oversight for this production differs globally. Manufacturing agents within a Good Manufacturing Practice (GMP) facility reduces the risk of the manufacturing process by including processes such as confirming the identity of the challenge agent and ascertaining that it's pure and free from impurities. However, in some cases it's not possible or feasible to manufacture to GMP standards, for example where the challenge agent requires an intermediate vector for growth. There is lack of clear guidance on what the minimum requirements for high-quality safe manufacture outside of GMP facilities should be and here we describe the development of a considerations document for the selection and production of challenge agents to meet this need.
PubMed: 35505774
DOI: 10.12688/wellcomeopenres.17869.1 -
Acta Biomaterialia Apr 2020Globally, chronic wounds impose a notable burden to patients and healthcare systems. Such skin wounds are readily subjected to bacteria that provoke inflammation and... (Review)
Review
Globally, chronic wounds impose a notable burden to patients and healthcare systems. Such skin wounds are readily subjected to bacteria that provoke inflammation and hence challenge the healing process. Furthermore, bacteria induce infection impeding re-epithelialization and collagen synthesis. With an estimated global market of $20.4 billion by 2021, appropriate wound dressing materials e.g. those composed of biopolymers originating from nature, are capable of alleviating the infection incidence and of accelerating the healing process. Particularly, biopolymeric nanofibrous dressings are biocompatible and mostly biodegradable and biomimic the extracellular matrix structure. Such nanofibrous dressings provide a high surface area and the ability to deliver antibiotics and antibacterial agents locally into the wound milieu to control infection. In this regard, with the dangerous evolution of antibiotic resistant bacteria, antibiotic delivery systems are being gradually replaced with antibacterial biohybrid nanofibrous wound dressings. This emerging class of wound dressings comprises biopolymeric nanofibers containing antibacterial nanoparticles, nature-derived compounds and biofunctional agents. Here, the most recent (since 2015) developments of antibacterial biopolymeric nanofibrous wound dressings, particularly those made of biohybrids, are reviewed and their antibacterial efficiency is evaluated based on a comprehensive literature analysis. Lastly, the prospects and challenges are discussed to draw a roadmap for further progresses and to open up future research avenues in this area. STATEMENT OF SIGNIFICANCE: With a global market of $20.4 billion by 2021, skin wound dressings are a crucial segment of the wound care industry. As an advanced class of bioactive wound dressing materials, natural polymeric nanofibers loaded with antibacterial agents, e.g. antimicrobial nanoparticles/ions, nature-derived compounds and biofunctional agents, have shown a remarkable potential for replacement of their classic counterparts. Also, given the expanding concern regarding antibiotic resistant bacteria, such biohybrid nanofibrous wound dressings can outperform classical drug delivery systems. Here, an updated overview of the most recent (since 2015) developments of antibacterial biopolymeric nanofibrous wound dressings is presented. In this review, while discussing about the antibacterial efficiency of such systems, the prospects and challenges are highlighted to draw a roadmap for further progresses in this area.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bandages; Honey; Humans; Nanofibers; Oils, Volatile; Plant Extracts; Polysaccharides; Proteins; Wound Healing
PubMed: 32084600
DOI: 10.1016/j.actbio.2020.02.022 -
Molecules (Basel, Switzerland) Jul 2019The synthesis and application of porphyrins has seen a huge shift towards research in porphyrin bio-molecular based systems in the past decade. The preferential... (Review)
Review
The synthesis and application of porphyrins has seen a huge shift towards research in porphyrin bio-molecular based systems in the past decade. The preferential localization of porphyrins in tumors, as well as their ability to generate reactive singlet oxygen and low dark toxicities has resulted in their use in therapeutic applications such as photodynamic therapy. However, their inherent lack of bio-distribution due to water insolubility has shifted research into porphyrin-nanomaterial conjugated systems to address this challenge. This has broadened their bio-applications, viz. bio-sensors, fluorescence tracking, in vivo magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT imaging to photo-immuno-therapy just to highlight a few. This paper reviews the unique theranostic role of porphyrins in disease diagnosis and therapy. The review highlights porphyrin conjugated systems and their applications. The review ends by bringing current challenges and future perspectives of porphyrin based conjugated systems and their respective applications into light.
Topics: Animals; Glycoconjugates; Humans; Magnetic Resonance Imaging; Mice; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Positron-Emission Tomography; Singlet Oxygen; Theranostic Nanomedicine; Water
PubMed: 31340553
DOI: 10.3390/molecules24142669 -
New Microbes and New Infections Nov 2020At the end of 2019, the novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, China, then spread rapidly across the country and throughout the world. The causative... (Review)
Review
At the end of 2019, the novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, China, then spread rapidly across the country and throughout the world. The causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); according to the International Committee on Taxonomy of Viruses, this virus has a nucleic acid sequence that is different from other known coronaviruses but has some similarity to the beta coronavirus identified in bats. Coronaviruses are a large virus group of enveloped positive-sense single-stranded RNA. They are divided into four genera-alpha, beta, delta and gamma-and alpha and beta coronaviruses are known to infect humans. Rapid and early diagnosis of COVID-19 is a challenging issue for physicians and other healthcare personnel. The sensitivity and specificity of the clinical, radiologic and laboratory tests used to diagnose COVID-19 are variable and largely differ in efficacy depending on the disease's stage of presentation.
PubMed: 32953123
DOI: 10.1016/j.nmni.2020.100761