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A major challenge for clinical management of melanoma is the prevention and treatment of metastatic disease. Drug discovery efforts over the last 10â years have resulted in several drugs that improve the prognosis of metastatic melanoma; however, most patients develop early resistance to these treatments. We designed and synthesized, through a concise synthetic strategy, a series of hybrid olefin-pyridinone compounds that consist of structural motifs from tamoxifen and ilicicolin H. These compounds were tested against a human melanoma cell line and patient-derived melanoma cells that had metastasized to the brain. Three compounds 7 b, 7 c, and 7 g demonstrated promising activity (IC50=0.4-4.3â µM). Cell cycle analysis demonstrated that 7 b and 7 c induce cell cycle arrest predominantly in the G1 phase. Both 7 b and 7c significantly inhibited migration of A375 melanoma cells; greater effects were demonstrated by 7 b. Molecular modelling analysis provides insight into a plausible mechanism of action.
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Antineoplásicos , Melanoma , Humanos , Melanoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Apoptose , Tamoxifeno , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Social media platforms are increasingly being used by stakeholders to generate, access, and share health-related information and experiences. Lung cancer is the most common cancer, impacting > 2 million patients globally. This observational study utilized a social listening approach to analyze social media trends and gain insights into stakeholder perceptions of lung cancer. METHODS: This social media study retrospectively collated data from open access blogs, forums, and social networking sites. Social media posts were collected between June 2019-May 2020 from 14 European countries. Using social media aggregator tools, posts comprising lung cancer and non-small cell lung cancer-specific terms were extracted. Manual and automated relevancy algorithms filtered the extracted information to provide the relevant dataset. This contextualized dataset was further mined to generate the final data for analysis. RESULTS: Of 1360 conversations analyzed, 42% were generated by patients/caregivers and 14% by healthcare professionals (HCPs). A majority of patients were 51-70 years old (approximately 50%) and 91% (n = 500/550) had late-stage cancer. Treatment (35%) and disease awareness (30%) were among the most discussed topic of the patient journey. Although the overall treatment sentiment was neutral, chemotherapy was the treatment type with the highest associated negative sentiment (28%); fewer negative sentiments were associated with immunotherapy (9%) and targeted therapy (2%), due to perceptions of longer survival outcomes and fewer side effects. In conversations that discussed clinical endpoints, "survivability" and "overall survival" (47 and 30%, respectively; n = 539) were most frequently mentioned by stakeholders. HCPs mostly used technical terms, whereas patients and caregivers used colloquial terms such as "getting rid of cancer". Emotional wellness was identified to have a huge impact on quality of life in lung cancer. Delay or treatment cancellations due to COVID-19, lack of effective treatments and funding, and lack of empathy by physicians emerged as the key unmet needs among patients/caregivers. CONCLUSIONS: Social listening proved to be an effective tool to explore stakeholders' perceptions and their key unmet needs, typically not available in published literature or databases, and provides HCPs with valuable insights into the distress, doubts, and needs of lung cancer patients and caregivers.
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COVID-19 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mídias Sociais , Idoso , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Neoplasias Pulmonares/terapia , Pessoa de Meia-Idade , Qualidade de Vida , Estudos RetrospectivosRESUMO
Polymorphism in drugs and bioactive molecules is not uncommon, and it has remained as one of the critical issues in drug development processes. While improving physicochemical properties of bioactive molecules has been a prime focus of the pharmaceutical chemists, not much efforts have been put toward the improvement of their potency via polymorphic modifications. Here, we consider five cases of 5-arylidene-2-aminothiazolidinones derivatives, the known anticancer agents, and discover eights polymorphs in three out of the five cases. We perform systematic crystallization experiments and detailed crystal structure analysis of the eight polymorphs and two compounds, estimate both their energetic and thermal stabilities, and compare their solid state properties. We also compare in-solution properties, e.g., equilibrium solubility, intrinsic dissolution rate, and phase stability, of three polymorphs of one of the cases. Further, we study the extent of inhibition imposed by those eight polymorphs and seven bulk and crystal forms of the compounds on the proliferation of MCF7 breast cancer cells and also the extent of their binding to the isozyme γ-enolase. Furthermore, we perform MD simulations on the eight polymorphs and one compound to estimate and compare their binding affinity with γ-enolase. Our experimental and MD simulation analyses in general emphasize the importance of polymorphism in improving the biological potency of individual molecules.
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Fosfopiruvato Hidratase , Cristalização , SolubilidadeRESUMO
Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is an emerging therapeutic target for a spectrum of human diseases. NX-13 is a small molecule therapeutic designed to target and activate NLRX1 to induce immunometabolic changes resulting in lower inflammation and therapeutic responses in inflammatory bowel disease (IBD). This study investigates the safety of NX-13 in a seven-day, repeat-dose general toxicity study in male and female Sprague Dawley rats at oral doses of 500 and 1000 mg/kg. Weights, clinical signs, functional observational battery, clinical pathology and histopathology were used for evaluation. Daily oral dosing of NX-13 up to 1000 mg/kg did not result in any changes in weight, abnormal clinical signs or behavior. No significant differences were observed between treated and control rats in hematology or blood biochemistry. Histopathological evaluation of 12 tissues demonstrated no differences between controls and treated rats. There were no changes in weights of brain, heart, kidney, liver or spleen. Pharmacokinetic analysis of a single oral dose of NX-13 at 10 mg/kg in Sprague Dawley rats provided a maximum plasma concentration of 57 ng/mL at 0.5 h post-dose. Analysis of colon tissue after oral dosing with 1 and 10 mg/kg indicated high peak concentrations (10 and 100 µg/g, respectively) that scale in a dose-proportional manner. These experiments suggest that NX-13 is safe and well-tolerated in rats given oral doses as high as 1000 mg/kg with a favorable gastrointestinal localized pharmacokinetic profile, confirming NX-13 as a promising therapeutic for Crohn's disease and ulcerative colitis.
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Doenças Inflamatórias Intestinais , Roedores , Administração Oral , Animais , Feminino , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Piridinas , Ratos , Ratos Sprague-DawleyRESUMO
Inflammatory bowel disease (IBD) is an expanding autoimmune disease afflicting millions that remains difficult to treat due to the accumulation of multiple immunological changes. BT-11 is an investigational new drug for IBD that is orally active, gut restricted, and targets the lanthionine synthetase C-like 2 immunometabolic pathway. CD25+ FOXP3+ CD4+ T cells are increased locally within the colon of BT-11-treated mice in Citrobacter rodentium and IL-10-/- mouse models of colitis. The maintained efficacy of BT-11 in the absence of IL-10 combined with the loss of efficacy when direct cell-cell interactions are prevented suggest that the regulatory T cell (Treg)-related elements of suppression are cell contact-mediated. When PD-1 is inhibited, both in vitro and in vivo, the efficacy of BT-11 is reduced, validating this assertion. The depletion of CD25+ cells in vivo abrogated the retention of therapeutic efficacy postdiscontinuation of treatment, indicating that Tregs are implicated in the maintenance of tolerance mediated by BT-11. Furthermore, the involvement of CD25 suggested a role of BT-11 in IL-2 signaling. Cotreatment with BT-11 and IL-2 greatly enhances the differentiation of CD25+ FOXP3+ cells from naive CD4+ T cells relative to either alone. BT-11 enhances phosphorylation of STAT5, providing a direct linkage to the regulation of FOXP3 transcription. Notably, when STAT5 is inhibited, the effects of BT-11 on the differentiation of Tregs are blocked. BT-11 effectively enhances the IL-2/STAT5 signaling axis to induce the differentiation and stability of CD25+ FOXP3+ cells in the gastrointestinal mucosa to support immunoregulation and immunological tolerance in IBD.
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Benzimidazóis/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Doenças Inflamatórias Intestinais/imunologia , Piperazinas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Colite/imunologia , Mucosa Gástrica/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Inflammatory bowel disease (IBD) is a complex autoimmune disease with dysfunction in pattern-recognition responses, including within the NLR family. Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is a unique NLR with regulatory and anti-inflammatory functions resulting in protection from IBD in mouse models. NX-13 is an orally active, gut-restricted novel drug candidate that selectively targets and activates the NLRX1 pathway locally in the gut. In vitro and in vivo efficacy of NLRX1 activation by NX-13 was examined. Oral treatment with NX-13 alleviates disease severity, colonic leukocytic infiltration, and cytokine markers of inflammation in three mouse models of IBD (dextran sulfate sodium, Mdr1a-/-, and CD45RBhi adoptive transfer). Treatment of naive CD4+ T cells with NX-13 in vitro decreases differentiation into Th1 and Th17 subsets with increased oxidative phosphorylation and decreased NF-κB activation and reactive oxygen species. With stimulation by PMA/ionomycin, TNF-α, or H2O2, PBMCs from ulcerative colitis patients treated with NX-13 had decreased NF-κB activity, TNF-α+ and IFN-γ+ CD4+ T cells and overall production of IL-6, MCP1, and IL-8. NX-13 activates NLRX1 to mediate a resistance to both inflammatory signaling and oxidative stress in mouse models and human primary cells from ulcerative colitis patients with effects on NF-κB activity and oxidative phosphorylation. NX-13 is a promising oral, gut-restricted NLRX1 agonist for treating IBD.
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Derivados de Benzeno/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Proteínas Mitocondriais/metabolismo , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/agonistas , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies. Oral BT-11 did not cause any clinical signs of toxicity, biochemical or hematological changes, or macroscopic or microscopic changes to organs in 90-day repeat-dose toxicity studies in rats and dogs at doses up to 1,000 mg/kg/d. Oral BT-11 resulted in low systemic exposure in both rats (area under the curve exposure from t = 0 to t = 8 hours [AUC0-8] of 216 h × ng/mL) and dogs (650 h × ng/mL) and rapid clearance with an average half-life of 3 hours. BT-11 did not induce changes in respiratory function, electrocardiogram parameters, or behavior with single oral doses of 1,000 mg/kg/d. There was no evidence of mutagenic or genotoxic potential for BT-11 up to tested limit doses using an Ames test, chromosomal aberration assay in human peripheral blood lymphocytes, or micronucleus assay in rats. Therefore, nonclinical studies show BT-11 to be a safe and well-tolerated oral therapeutic with potential as a potent immunometabolic therapy for UC and CD with no-observed adverse effect level >1,000 mg/kg in in vivo studies.
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Benzimidazóis/farmacocinética , Benzimidazóis/toxicidade , Proteínas de Membrana/antagonistas & inibidores , Piperazinas/farmacocinética , Piperazinas/toxicidade , Administração Oral , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Ratos Wistar , Testes de ToxicidadeRESUMO
Natural products are the source of innumerable pharmaceutical drug candidates and also form an important aspect of herbal remedies. They are also a source of various bioactive compounds. Herein we have leveraged the structural attributes of several natural products in building a library of architecturally diverse chiral molecules by harnessing R-tryptophan as the chiral auxiliary. It is converted to its corresponding methyl ester 1 which in turn provided a bevy of 1-aryl-tetrahydro-ß-carbolines 2a-d, which were then converted to chiral compounds via a diversity oriented synthetic strategy (DOS). In general, intermolecular and intramolecular ring rearrangements facilitated the formation of the final compounds. Four different classes of molecules with distinct architectures were generated, adding up to nearly twenty-two individual molecules. Phenotypic screening of a representative section of the library revealed two molecules that selectively inhibit MCF7 breast cancer cells with IC50 of â¼5 µg mL-1 potency.
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Produtos Biológicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Células MCF-7 , Modelos Moleculares , Conformação Molecular , FenótipoRESUMO
OBJECTIVE: To assess the allele rs 1143634 in IL-1ß and rs1800587 in IL-1α in patients for orthodontically induced external apical root resorption (EARR). MATERIAL AND METHODS: Intra-oral periapical radiograph (IOPA) of maxillary incisors of 142 Patients were evaluated for resorption at two time points; before the start of fixed mechanotherapy (T1) and after one year of treatment (T2). The individuals with root resorption<2mm were categorized as a control group (group 1; n=90), and resorption>2mm were categorized as case group (group 2; n=52). Buccal swabs of all patients were taken and DNA could be isolated in 95 out of 142 samples (group 1 {n=58}, group 2 {n=37}), which were then screened for the selected two polymorphic targets to determine the nucleotide status of these targets. Tetra-primer ARMS PCR reactions were carried out using all 4 primers for each polymorphism. RESULTS: rs11800587 was not associated with risk of EARR in any inheritance model. Chi-square test for association of alleles with EARR revealed that rs1143634 was associated with the risk of EARR in an allelic model in such a way that A allele of this SNP increased the risk of EARR 4 folds [OR=4.375; P=0.016]. However, the adjusted level of significance using the Holm-Bonferroni method for rs1143634 was P<0.010 for A and G comparison rendering the results non-significant. CONCLUSION: SNP rs1143634 and SNP rs11800587 were not associated with risk of EARR in any inheritance model.
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Interleucina-1alfa , Interleucina-1beta , Polimorfismo de Nucleotídeo Único , Reabsorção da Raiz , Adolescente , Criança , Feminino , Humanos , Masculino , Adulto Jovem , Alelos , Estudos de Casos e Controles , Incisivo , Interleucina-1alfa/genética , Interleucina-1beta/genética , Reabsorção da Raiz/genética , Reabsorção da Raiz/etiologiaRESUMO
Agriculture Internet of Things (AIoTs) deployments require design of high-efficiency Quality of Service (QoS) & security models that can provide stable network performance even under large-scale communication requests. Existing security models that use blockchains are either highly complex or require large delays & have higher energy consumption for larger networks. Moreover, the efficiency of these models depends directly on consensus-efficiency & miner-efficiency, which restricts their scalability under real-time scenarios. To overcome these limitations, this study proposes the design of an efficient Q-Learning bioinspired model for enhancing QoS of AIoT deployments via customized shards. The model initially collects temporal information about the deployed AIoT Nodes, and continuously updates individual recurring trust metrics. These trust metrics are used by a Q-Learning process for identification of miners that can participate in the block-addition process. The blocks are added via a novel Proof-of-Performance (PoP) based consensus model, which uses a dynamic consensus function that is based on temporal performance of miner nodes. The PoP consensus is facilitated via customized shards, wherein each shard is deployed based on its context of deployment, that decides the shard-length, hashing model used for the shard, and encryption technique used by these shards. This is facilitated by a Mayfly Optimization (MO) Model that uses PoP scores for selecting shard configurations. These shards are further segregated into smaller shards via a Bacterial Foraging Optimization (BFO) Model, which assists in identification of optimal shard length for underlying deployment contexts. Due to these optimizations, the model is able to improve the speed of mining by 4.5%, while reducing energy needed for mining by 10.4%, improving the throughput during AIoT communications by 8.3%, and improving the packet delivery consistency by 2.5% when compared with existing blockchain-based AIoT deployment models under similar scenarios. This performance was observed to be consistent even under large-scale attacks.
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The increasing prevalence of gout has been accompanied by a growing number of patients intolerant to or with disease refractory to the available urate-lowering therapies. This metabolic disease is a common disease with a higher prevalence in men older than 30 years and in women older than 50 years. These findings highlight the need for emerging treatments to effectively lower urate levels. In this view, we describe the xanthine oxidase (XO) inhibitory activities of the synthesized compounds 5a-j and also their antioxidant activities. Compounds 5c, 5d, 5f, 5h, and 5j exhibited good inhibitory activities against XO. On the other hand, compounds 5g and 5j exhibited moderate antioxidant activity.
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Antioxidantes/síntese química , Antioxidantes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Xantina Oxidase/antagonistas & inibidores , Animais , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Supressores da Gota/síntese química , Supressores da Gota/farmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Ácido Úrico/metabolismo , Xantina Oxidase/metabolismoRESUMO
The purpose of the study was to report a unique case of Klebsiella keratitis presenting as a ring infiltrate in an adolescent girl. A 16-year-old girl presented with decreased vision in the right eye preceding an episode of fever with a rash associated with burning micturition. The patient was examined after taking appropriate consent. The slit-lamp examination revealed a ring-shaped corneal infiltrate with an epithelial defect in her right eye. Corneal scrapings were sent for microbiological evaluation which revealed Gram-negative rods and culture identified it as extended-spectrum beta-lactamase-producing Klebsiella pneumoniae colonies. The patient showed a good response to topical fortified amikacin and tobramycin. For her systemic complaints, the pediatrician did a thorough investigative workup out of which blood culture showed growth of K. pneumoniae. Hence, intravenous antibiotics were given based on the antibiogram report and the patient recovered. After 2 weeks, a paracentral infiltrate in her left eye was noted followed by anterior uveitis. The patient responded well to the topical course of steroids along with aminoglycosides. Four months later, she had a recurrence of anterior uveitis in the right eye preceded by fever. Blood investigations were negative. Hence, a diagnosis of recurrent uveitis secondary to endogenous infection was made and the patient was successfully treated with a short course of topical steroids. The patient is on follow-up for the past 6 months and maintaining the best-corrected visual acuity of 20/20 OU with normal intraocular pressure and quiet anterior chamber (AC). This is the first clinical report describing a ring infiltrate in endogenous Klebsiella keratitis and emphasizes thorough workup for prompt treatment.
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Introduction: Bloodstream infections in the intensive care unit have always been a global healthcare challenge. The present study was conducted with the aim to evaluate the yearly trend of antibiotic resistance in non-fermenting Gram-negative bacilli (NFGNB) causing septicemia in intensive care units. Methods: Blood samples were collected from the patients admitted in various intensive care units and processed for isolation and identification of non-fermenting Gram-negative bacilli. The isolated bacterial strains were subjected to antibiotic susceptibility testing as per standard operating procedures. Results: Out of 3632 blood samples, 977 (26.9%) samples showed microbial growth, of which 10.1% were Gram positive cocci, 8.7% were Gram negative bacilli (Enterobacterales), 7% were NFGNB and 1% were Candida spp. Increasing resistance among Acinetobacter baumannii complex was observed to ceftazidime, cefepime, amikacin, ciprofloxacin, levofloxacin, meropenem and trimethoprim-sulfamethoxazole. Moreover, Pseudomonas aeruginosa strains were found to be associated with increased resistance to ciprofloxacin, levofloxacin, ceftazidime and meropenem. A substantial increase in resistance levels was observed among Stenotrophomonas maltophilia and Sphingomonas paucimobilis as well. Conclusions: An increasing trend of antimicrobial resistance in NFGNB envisages the worst consequences in ICUs in the coming years. Therefore, reviewing and strict implementation of the antimicrobial policies including 'rational use of antibiotics' is recommended.
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COVID-19 is a complex disease with short-term and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. As many drugs targeting single targets showed only limited effectiveness against COVID-19, here, we aimed to explore a multi-target strategy. We synthesized a focused compound library based on C2-substituted indolealkylamines (tryptamines and 5-hydroxytryptamines) with activity for three potential COVID-19-related proteins, namely melatonin receptors, calmodulin and human angiotensin converting enzyme 2 (hACE2). Two molecules from the library, 5e and h, exhibit affinities in the high nanomolar range for melatonin receptors, inhibit the calmodulin-dependent calmodulin kinase II activity and the interaction of the SARS-CoV-2 Spike protein with hACE2 at micromolar concentrations. Both compounds inhibit SARS-CoV-2 entry into host cells and 5h decreases SARS-CoV-2 replication and MPro enzyme activity in addition. In conclusion, we provide a proof-of-concept for the successful design of multi-target compounds based on the tryptamine scaffold. Optimization of these preliminary hit compounds could potentially provide drug candidates to treat COVID-19 and other coronavirus diseases.
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COVID-19 , Humanos , SARS-CoV-2 , Tratamento Farmacológico da COVID-19 , Calmodulina , Receptores de MelatoninaRESUMO
The most prevalent infection in the world is dermatophytosis, which is a major issue with high recurrence and can affect the entire body including the skin, hair, and nails. The major goal of this Review is to acquire knowledge about cutting-edge approaches for treating dermatophytosis efficiently by adding antifungals to formulations based on nanocarriers in order to overcome the shortcomings of standard treatment methods. Updates on nanosystems and research developments on animal and clinical investigations are also presented. Along with the currently licensed formulations, the investigation also emphasizes novel therapies and existing therapeutic alternatives that can be used to control dermatophytosis. The Review also summarizes recent developments on the prevalence, management approaches, and disadvantages of standard dosage types. There are a number of therapeutic strategies for the treatment of dermatophytosis that have good clinical cure rates but also drawbacks such as antifungal drug resistance and unfavorable side effects. To improve therapeutic activity and get around the drawbacks of the traditional therapy approaches for dermatophytosis, efforts have been described in recent years to combine several antifungal drugs into new carriers. These formulations have been successful in providing improved antifungal activity, longer drug retention, improved effectiveness, higher skin penetration, and sustained drug release.
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BACKGROUND: Graft-versus-host disease (GVHD) is the major cause of short- and long-term morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Treatment options beyond corticosteroid therapy remain limited, and prolonged treatment often leads to impaired quality of life (QoL). A better understanding of the needs and experiences of patients with GVHD is required to improve patient care. OBJECTIVE: The aim of this study is to explore different social media (SM) channels for gathering and analyzing the needs and experiences of patients and other stakeholders across 14 European countries. METHODS: We conducted a retrospective analysis of SM data from the public domain. The Talkwalker social analytics tool collected data from open-access forums, blogs, and various social networking sites using predefined search strings. The raw data set derived from the aggregator tool was automatically screened for the relevancy of posts, generating the curated data set that was manually reviewed to identify posts that fell within the predefined inclusion and exclusion criteria. This final data set was then used for the deep-dive analysis. RESULTS: A total of 9016 posts relating to GVHD were identified between April 2019 and April 2021. Deduplication and relevancy checks resulted in 325 insightful posts, with Twitter contributing 250 (77%) posts; blogs, 49 (15%) posts; forums, 13 (4%) posts; Facebook, 7 (2%) posts; and Instagram and YouTube, 4 (1%) posts. Patients with GVHD were the primary stakeholders, contributing 63% of all SM posts. In 234 posts, treatment was the most discussed stage of the patient journey (68%), followed by symptoms (33%), and diagnosis and tests (21%). Among treatment-related posts (n=159), steroid therapy was most frequently reported (54/159, 34%). Posts relating to treatment features (n=110) identified efficacy (45/110, 41%), side effects (38/110, 35%), and frequency and dosage (32/110, 29%), as the most frequently discussed features. Symptoms associated with GVHD were described in 24% (77/325) of posts, including skin-related conditions (49/77, 64%), dry eyes or vision change (13/77, 17%), pain and cramps (16/77, 21%), and fatigue or muscle weakness (12/77, 16%). The impacts of GVHD on QoL were discussed in 51% (165/325) of all posts, with the emotional, physical and functional, social, and financial impacts mentioned in 69% (114/165), 50% (82/165), 5% (8/165), and 2% (3/165) of these posts, respectively. Unmet needs were reported by patients or caregivers in 24% (77/325) of analyzed conversations, with treatment-related side effects being the most common (35/77, 45%) among these posts. CONCLUSIONS: SM listening is a useful tool to identify medical needs. Treatment of GVHD, including treatment-related side effects, as well as its emotional and physical impact on QoL, are the major topics that GVHD stakeholders mention on SM. We encourage a structured discussion of these topics in interactions between health care providers and patients with GVHD. TRIAL REGISTRATION: Not applicable.
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Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.
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Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Ratos , Animais , Antibacterianos/farmacologia , Proteômica , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Background: Despite a wealth of real-world data on metastatic breast cancer (mBC), insights into the lived experience are lacking. This study aimed to explore how the lived experience of mBC is described on social media. Methods: A predefined search string identified posts relevant to the lived experience of mBC from Twitter, patient forums, and blogs across 14 European countries. The final data set was analyzed using content analysis. Results: A total of 76,456 conversations were identified between November 1, 2018, and November 30, 2020. Twitter was the most commonly used social media platform across all 76,456 conversations from the raw data set (n = 61,165; 80%). Automated and manual relevancy checks followed by a final random sampling filter identified 820 conversations for content analysis. The majority of data from the raw data set was generated from the United Kingdom (n = 31,346; 41%). From this final data set, 61% of posts were authored by patients, 15% by friends and/or family members of patients, and 14% by caregivers. A total of 686 conversations described the patient journey (n = 686/820; 84%); 64% of these (n = 439) concerned breast cancer treatment, with approximately 40% of discussions regarding diagnosis and tests (n = 274/686) and less than 20% of discussions surrounding disease management (n = 123/686; 18%). Key themes relating to a lack of effective treatment, prolonged survival and associated quality of life, debilitating consequences of side effects, and the social impacts of living with mBC were identified. Conclusions: The findings from this study provided an insight into the lived experience of mBC. While retrospective data collection inherently limits the amount of demographic or clinical information that can be obtained from the population sample, social media listening studies offer training to healthcare professionals in communication, the importance of quality of life, organization of healthcare, and even the design of clinical trials. As new targeted therapies are gradually incorporated into clinical practice, innovative technologies, such as social media listening, have the potential to support regulatory procedures and drug toxicity monitoring, as well as provide the patient voice in the regulation of new and existing medicines.
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BACKGROUND: Cutaneous melanoma is an aggressive malignancy that is proposed to account for 90% of skin cancer-related mortality. Individuals with melanoma experience both physical and psychological impacts associated with their diagnosis and treatment. Health-related information is being increasingly accessed and shared by stakeholders on social media platforms. OBJECTIVE: This study aimed to assess how individuals living with melanoma across 14 European countries use social media to discuss their needs and provide their perceptions of the disease. METHODS: Social media sources including Twitter, forums, and blogs were searched using predefined search strings of keywords relating to melanoma. Manual and automated relevancy approaches filtered the extracted data for content that provided patient-centric insights. This contextualized data was then mined for insightful concepts around the symptoms, diagnosis, treatment, impacts, and lived experiences of melanoma. RESULTS: A total of 182,400 posts related to melanoma were identified between November 2018 and November 2020. Following exclusion of irrelevant posts and using random sampling methodology, 864 posts were identified as relevant to the study objectives. Of the social media channels included, Twitter was the most commonly used, followed by forums and blogs. Most posts originated from the United Kingdom (n=328, 38%) and Spain (n=138, 16%). Of the relevant posts, 62% (n=536) were categorized as originating from individuals with melanoma. The most frequently discussed melanoma-related topics were treatment (436/792, 55%), diagnosis and tests (261/792, 33%), and remission (190/792, 24%). The majority of treatment discussions were about surgery (292/436, 67%), followed by immunotherapy (52/436, 12%). In total, 255 posts discussed the impacts of melanoma, which included emotional burden (n=179, 70%), physical impacts (n=61, 24%), effects on social life (n=43, 17%), and financial impacts (n=10, 4%). CONCLUSIONS: Findings from this study highlight how melanoma stakeholders discuss key concepts associated with the condition on social media, adding to the conceptual model of the patient journey. This social media listening approach is a powerful tool for exploring melanoma stakeholder perspectives, providing insights that can be used to corroborate existing data and inform future studies.
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The impact of elevated temperature at the reproductive stage of a crop is one of the critical limitations that influence crop growth and productivity globally. This study was aimed to reveal how sowing time and changing field temperature influence on the regulation of oxidative stress indicators, antioxidant enzymes activity, soluble sugars (SS), and amino acids (AA) in Indian Mustard. The current study was carried out during the rabi 2017-2018 and 2018-2019 where, five varieties of mustard viz. Pusa Mustard 25 (PM-25) (V1), PM-26 (V2), BPR-541-4 (V3), RH-406 (V4), and Urvashi (V5) were grown under the field conditions on October 30 (normal sowing; S1), November 18 (late sowing; S2) and November 30 (very late sowing; S3) situations. The S1 and S3 plants, at mid-flowering stage, showed a significant variation in accumulation of SS (8.5 and 17.3%), free AA (235.4 and 224.6%), and proline content (118.1 and 133%), respectively, and played a crucial role in the osmotic adjustment under stress. The results showed that S3 sowing, exhibited a significant induction of the hydrogen peroxide (H2O2) (110.2 and 86.6%) and malondialdehyde (23.5 and 47.5%) concentrations, respectively, which indicated the sign of oxidative stress in plants. Interestingly, the polyphenol oxidase, peroxidase, superoxide dismutase, and catalase enzyme activities were also significantly increased in S3 plants compared to S1 plants, indicating their significant roles in ameliorating the oxidative stress. Furthermore, the concentration of fatty acid levels such as palmitic, stearic, oleic, and linoleic acids level also significantly increased in S3 plants, which influenced the seed and oil quality. The study suggests that the late sowing significantly impaired the biochemical mechanisms in Indian mustard. Further, the mustard variety V4 (RH-406) was found to be effective for cultivation as well as environmental stress adoption in Indian soils, and it could be highly useful in breeding for developing heat-tolerant genotypes for ensuring the food security.