Aplasia medular asociada a osimertinib: a propósito de un caso / Bone marrow aplasia associated with osimertinib: a case report

Osimertinib es un inhibidor de tirosina quinasa (ITK) de tercera generación aprobado para el cáncer de pulmón no microcítico localmente avanzado o metastásico con mutación del EGFR. La prevalencia de efectos adversos hematológicos graves asociados a este fármaco es infrecuente según ficha técnica. Se describe el caso de una mujer de 69 años diagnosticada de cáncer de pulmón no microcítico localmente avanzado en tratamiento con osimertinib en primera línea con aparición de trombocitopenia severa que requirió de ingresos hospitalarios, transfusiones de sangre y plaquetas y de tratamiento con eltrombopag sin conseguir resultados favorables para la paciente. (AU)

Osimertinib is a third generation, tyrosine kinase inhibitor (TKI) approved for locally advanced or metastatic non-small cell lung cancer with EGFR mutation. The prevalence of serious haematological adverse events associated with osimertinib is uncommon according to the summary of product characteristics. The case of study describes a 69-year-old woman diagnosed with locally advanced non-small cell lung cancer treated with osimertinib, with onset of severe thrombocytopenia that required hospital admissions, blood and platelet transfusions, and treatment with eltrombopag, without achieving favourable results. (AU)

DNA recognition and induced genome modification by a hydroxymethyl-γ tail-clamp peptide nucleic acid.

Peptide nucleic acids (PNAs) can target and stimulate recombination reactions in genomic DNA. We have reported that γPNA oligomers possessing the diethylene glycol γ-substituent show improved efficacy over unmodified PNAs in stimulating recombination-induced gene modification. However, this structural modification poses a challenge because of the inherent racemization risk in O-alkylation of the precursory serine side chain. To circumvent this risk and improve γPNA accessibility, we explore the utility of γPNA oligomers possessing the hydroxymethyl-γ moiety for gene-editing applications. We demonstrate that a γPNA oligomer possessing the hydroxymethyl modification, despite weaker preorganization, retains the ability to form a hybrid with the double-stranded DNA target of comparable stability and with higher affinity than that of the diethylene glycol-γPNA. When formulated into poly(lactic-co-glycolic acid) nanoparticles, the hydroxymethyl-γPNA stimulates higher frequencies (≥ 1.5-fold) of gene modification than the diethylene glycol γPNA in mouse bone marrow cells.

Altering Fish Behavior by Sensing Swarm Patterns of Fish in an Artificial Aquatic Environment Using an Interactive Robotic Fish.

Numerous studies have been conducted to prove the calming and stress-reducing effects on humans of visiting aquatic environments. As a result, many institutions have utilized fish to provide entertainment and treat patients. The most common issue in this approach is controlling the movement of fish to facilitate human interaction. This study proposed an interactive robot, a robotic fish, to alter fish swarm behaviors by performing an effective, unobstructed, yet necessary, defined set of actions to enhance human interaction. The approach incorporated a minimalistic but futuristic physical design of the robotic fish with cameras and infrared (IR) sensors, and developed a fish-detecting and swarm pattern-recognizing algorithm. The fish-detecting algorithm was implemented using background subtraction and moving average algorithms with an accuracy of 78%, while the swarm pattern detection implemented with a Convolutional Neural Network (CNN) resulted in a 77.32% accuracy rate. By effectively controlling the behavior and swimming patterns of fish through the smooth movements of the robotic fish, we evaluated the success through repeated trials. Feedback from a randomly selected unbiased group of subjects revealed that the robotic fish improved human interaction with fish by using the proposed set of maneuvers and behavior.

Antispacer peptide nucleic acids for sequence-specific CRISPR-Cas9 modulation.

Despite the rapid and broad implementation of CRISPR-Cas9-based technologies, convenient tools to modulate dose, timing, and precision remain limited. Building on methods using synthetic peptide nucleic acids (PNAs) to bind RNA with unusually high affinity, we describe guide RNA (gRNA) spacer-targeted, or 'antispacer', PNAs as a tool to modulate Cas9 binding and activity in cells in a sequence-specific manner. We demonstrate that PNAs rapidly and efficiently target complexed gRNA spacer sequences at low doses and without design restriction for sequence-selective Cas9 inhibition. We further show that short PAM-proximal antispacer PNAs achieve potent cleavage inhibition (over 2000-fold reduction) and that PAM-distal PNAs modify gRNA affinity to promote on-target specificity. Finally, we apply antispacer PNAs for temporal regulation of two dCas9-fusion systems. These results present a novel rational approach to nucleoprotein engineering and describe a rapidly implementable antisense platform for CRISPR-Cas9 modulation to improve spatiotemporal versatility and safety across applications.

Peptide nucleic acids and their role in gene regulation and editing.

The unique properties of peptide nucleic acid (PNA) makes it a desirable candidate to be used in therapeutic and biotechnological interventions. It has been broadly utilized for numerous applications, with a major focus in regulation of gene expression, and more recently in gene editing. While the classic PNA design has mainly been employed to date, chemical modifications of the PNA backbone and nucleobases provide an avenue to advance the technology further. This review aims to discuss the recent developments in PNA based gene manipulation techniques and the use of novel chemical modifications to improve the current state of PNA mediated gene targeting.

Adjuvant Therapy for High-risk Endometrial Carcinoma.

About one-fifth of endometrial cancers are 'high risk', which carries a poorer prognosis. Management strategies to optimise their survival have been under investigation for many years. Despite recent advances, their overall survival remains relatively poor. The definition of high risk in endometrial cancers has been based on clinicopathological factors until recently, when molecular profiling has shown greater discrimination. There is, however, poor correlation between traditional clinicopathological factors and their molecular profile. This is the subject of ongoing trials to better individualise adjuvant post-hysterectomy treatment. The management of high-risk tumours is traditionally based on surgery followed by radiotherapy, despite no proven overall survival benefit in early stages. The place of chemotherapy remains under investigation, with recent trials showing benefit in more advanced stages. The Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) and Gynecologic Oncology Group trials support the use of chemoradiation and chemotherapy for stage III and adverse histological subgroups. In addition, there is now early evidence of correlation between benefit from adjuvant chemotherapy based on molecular alterations in the tumour cells. In this review, we look at the current evidence on management strategies in the evolving era of molecular diagnosis and stratification.

Synthesis of ( R)- and ( S)-Fmoc-Protected Diethylene Glycol Gamma PNA Monomers with High Optical Purity.

A robust synthetic route has been developed for preparing optically pure, Fmoc-protected diethylene glycol-containing ( R)- and ( S)-γPNA monomers. The strategy involves the application of 9-(4-bromophenyl)-9-fluorenyl as a temporary, safety-catch protecting group for the suppression of epimerization in the O-alkylation and reductive amination steps. The optical purities of the final monomers were determined to be greater than 99.5% ee, as assessed by 19F-NMR and HPLC. The new synthetic methodology is well-suited for large-scale monomer production, with most synthetic steps providing excellent chemical yields without the need for chromatographic purification other than a simple workup and precipitation.

Prospective multinational serosurveillance study of Bordetella pertussis infection among 10- to 18-year-old Asian children and adolescents.

OBJECTIVES: Bordetella pertussis continues to cause outbreaks worldwide. To assess the role of children and adolescent in transmission of pertussis in Asia, we performed a multinational serosurveillance study. METHODS: From July 2013 to June 2016, individuals aged 10 to 18 years who had not received any pertussis-containing vaccine within the prior year were recruited in 10 centres in Asia. Serum anti-pertussis toxin (PT) IgG was measured by ELISA. Demographic data and medical histories were obtained. In the absence of pertussis immunization, anti-PT IgG ≥62.5 IU/mL was interpreted as B. pertussis infection within 12 months prior, among them levels ≥125 IU/mL were further identified as infection within 6 months. RESULTS: A total of 1802 individuals were enrolled. Anti-PT IgG geometric mean concentration was 4.5, and 87 (4.8%) individuals had levels ≥62.5 IU/mL; among them, 73 (83.9%) had received three or more doses of pertussis vaccine before age 6 years. Of 30 participants with persistent cough during the past 6 months, one (3.3%) had level ≥125 IU/mL. There was no significant difference in proportions with anti-PT IgG ≥62.5 IU/mL among age groups (13-15 vs. 10-12 years, 16-18 vs. 10-12 years), between types of diphtheria, pertussis and tetanus (DTP; whole cell vs. acellular), number of doses before age 6 years within the DTP whole-cell pertussis vaccine (five vs. four doses) or acellular pertussis vaccine (five vs. four doses) and history of persistent cough during the past 6 months (yes vs. no). CONCLUSIONS: There is significant circulation of B. pertussis amongst Asian children and adolescents, with one in 20 having serologic evidence of recent infection regardless of vaccination background.

Design of Bivalent Nucleic Acid Ligands for Recognition of RNA-Repeated Expansion Associated with Huntington's Disease.

We report the development of a new class of nucleic acid ligands that is comprised of Janus bases and the MPγPNA backbone and is capable of binding rCAG repeats in a sequence-specific and selective manner via, inference, bivalent H-bonding interactions. Individually, the interactions between ligands and RNA are weak and transient. However, upon the installation of a C-terminal thioester and an N-terminal cystine and the reduction of disulfide bond, they undergo template-directed native chemical ligation to form concatenated oligomeric products that bind tightly to the RNA template. In the absence of an RNA target, they self-deactivate by undergoing an intramolecular reaction to form cyclic products, rendering them inactive for further binding. The work has implications for the design of ultrashort nucleic acid ligands for targeting rCAG-repeat expansion associated with Huntington's disease and a number of other related neuromuscular and neurodegenerative disorders.

Shape selective bifacial recognition of double helical DNA.

An impressive array of antigene approaches has been developed for recognition of double helical DNA over the past three decades; however, few have exploited the 'Watson-Crick' base-pairing rules for establishing sequence-specific recognition. One approach employs peptide nucleic acid as a molecular reagent and strand invasion as a binding mode. However, even with integration of the latest conformationally-preorganized backbone design, such an approach is generally confined to sub-physiological conditions due to the lack of binding energy. Here we report the use of a class of shape-selective, bifacial nucleic acid recognition elements, namely Janus bases, for targeting double helical DNA or RNA. Binding occurs in a highly sequence-specific manner under physiologically relevant conditions. The work may provide a foundation for the design of oligonucleotides for targeting the secondary and tertiary structures of nucleic acid biopolymers.

Adaptation to Stressors by Systemic Protein Amyloidogenesis.

The amyloid state of protein organization is typically associated with debilitating human neuropathies and is seldom observed in physiology. Here, we uncover a systemic program that leverages the amyloidogenic propensity of proteins to regulate cell adaptation to stressors. On stimulus, cells assemble the amyloid bodies (A-bodies), nuclear foci containing heterogeneous proteins with amyloid-like biophysical properties. A discrete peptidic sequence, termed the amyloid-converting motif (ACM), is capable of targeting proteins to the A-bodies by interacting with ribosomal intergenic noncoding RNA (rIGSRNA). The pathological ß-amyloid peptide, involved in Alzheimer's disease, displays ACM-like activity and undergoes stimuli-mediated amyloidogenesis in vivo. Upon signal termination, elements of the heat-shock chaperone pathway disaggregate the A-bodies. Physiological amyloidogenesis enables cells to store large quantities of proteins and enter a dormant state in response to stressors. We suggest that cells have evolved a post-translational pathway that rapidly and reversibly converts native-fold proteins to an amyloid-like solid phase.

Intimate partner violence in Sri Lanka: a scoping review.

South Asia is considered to have a high prevalence of intimate partner violence (IPV) against women. Therefore the World Health Organisation has called for context-specific information about IPV from different regions. A scoping review of published and gray literature over the last 35 years was conducted using Arksey and O'Malley's framework. Reported prevalence of IPV in Sri Lanka ranged from 20-72%, with recent reports of rates ranging from 25- 35%. Most research about IPV has been conducted in a few provinces and is based on the experience of legally married women. Individual, family, and societal risk factors for IPV have been studied, but their complex relationships have not been comprehensively investigated. Health consequences of IPV have been reported, with particular attention to physical health, but women are likely to underreport sexual violence. Women seek support mainly from informal networks, with only a few visiting agencies to obtain help. Little research has focused on health sector responses to IPV and their effectiveness. More research is needed on how to challenge gendered perceptions about IPV. Researchers should capture the experience of women in dating/cohabiting relationships and women in vulnerable sectors (post-conflict areas and rural areas), and assess how to effectively provide services to them. A critical evaluation of existing services and programmes is also needed to advance evidence informed programme and policy changes in Sri Lanka.

Cancer cells exploit eIF4E2-directed synthesis of hypoxia response proteins to drive tumor progression.

Human tumors display considerable diversity in their genetic makeup but share common physiologic attributes such as a hypoxic microenvironment that contribute to the malignant phenotype. Hypoxic cells switch from eukaryotic initiation factor 4E (eIF4E) to eIF4E2 cap-dependent translation to synthesize a portion of their proteins. Here, we show that genetically distinct human cancer cells exploit eIF4E2-directed protein synthesis to form cellular masses larger than approximately 0.15 mm, the diffusion limit of oxygen. Cancer cells depleted of eIF4E2 are indistinguishable from control cells under normoxic conditions, but are unable to survive and proliferate in low oxygen conditions. Activation of eIF4E2-directed translation is essential for cancer cells to form a hypoxic tumor core in in vitro spheroids and to form detectable tumors in in vivo xenograft assays. In contrast, the eIF4E-directed protein synthesis pathway alone cannot sustain cellular adaptation to hypoxia in vitro or confer tumorigenic potential in xenograft assays. These data demonstrate that the phenotypic expression of the cancer genome requires translation by the eIF4E2-directed hypoxic protein synthesis machinery.

A prospective study of a ceramic-on-metal bearing in total hip arthroplasty. Clinical results, metal ion levels and chromosome analysis at two years.

We prospectively assessed the efficacy of a ceramic-on-metal (CoM) hip bearing with uncemented acetabular and femoral components in which cobalt-chrome acetabular liners and alumina ceramic heads were used. The cohort comprised 94 total hip replacements (THRs) in 83 patients (38 women and 45 men) with a mean age of 58 years (42 to 70). Minimum follow-up was two years. All patients had pre- and post-operative assessment using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), Oxford hip score and Short-Form 12 scores. All showed a statistically significant improvement from three months post-operatively onwards (all p < 0.001). After two years whole blood metal ion levels were measured and chromosomal analysis was performed. The levels of all metal ions were elevated except vanadium. Levels of chromium, cobalt, molybdenum and titanium were significantly higher in patients who underwent bilateral THR compared with those undergoing unilateral THR (p < 0.001). Chromosomal analysis demonstrated both structural and aneuploidy mutations. There were significantly more breaks and losses than in the normal population (p < 0.001). There was no significant difference in chromosomal aberration between those undergoing unilateral and bilateral procedures (all analyses p ≥ 0.62). The use of a CoM THR is effective clinically in the short-term, with no concerns, but the significance of high metal ion levels and chromosomal aberrations in the long-term remains unclear.

Association of levofloxacin resistance with mortality in adult patients with invasive pneumococcal diseases: a post hoc analysis of a prospective cohort.

OBJECTIVE: This study was conducted to identify risk factors for mortality and to evaluate the impact of antimicrobial resistance on outcome in adult patients with invasive pneumococcal disease (IPD). METHODS: A post hoc analysis of an observational cohort study on community-acquired pneumococcal infections was conducted and a total of 136 adult patients with IPD were analyzed in this study. RESULTS: Pneumonia was the most common type of infection (n = 84, 61.8 %), followed by primary bacteremia (n = 15, 11.0 %) and meningitis (n = 15, 11.0 %). One hundred and three patients (75.7 %) had concomitant pneumococcal bacteremia. The overall 30-day mortality rate was 26.5 % (36/136), and factors associated with 30-day mortality were corticosteroid use, presentation with septic shock, and development of acute respiratory distress syndrome (ARDS) (all P < 0.05). While penicillin and erythromycin resistance were associated with a lower mortality, an association between levofloxacin resistance and increased mortality was found in the univariate analysis; however, statistical significance was not reached (P = 0.083). Multivariable analysis showed that presentation with septic shock, corticosteroid use, development of ARDS, and levofloxacin resistance were independent factors associated with 30-day mortality. Of the five patients with IPD caused by levofloxacin-resistant Streptococcus pneumoniae, three (60 %) died within 30 days of diagnosis. CONCLUSION: Levofloxacin resistance was associated with increased mortality, along with septic shock, prior use of corticosteroids, and development of ARDS, in adult patients with IPD. Our data suggest that the emergence of levofloxacin resistance among invasive pneumococcal isolates is now becoming a challenge for clinicians managing community-acquired bacterial infections.

The present state of treatments for articular cartilage defects in the knee.

INTRODUCTION: Chondral and osteochondral lesions of the knee are notoriously difficult to treat due to the poor healing capacity of articular cartilage and the hostile environment of moving joints, ultimately causing disabling pain and early osteoarthritis. There are many different reconstructive techniques used currently but few are proven to be of value. However, some have been shown to produce a better repair with hyaline-like cartilage rather than fibrocartilage. METHODS: A systematic search of all available online databases including PubMed, MEDLINE(®) and Embase™ was undertaken using several keywords. All the multiple treatment options and methods available were considered. These were summarised, and the evidence for and against them was scrutinised. RESULTS: A total of 460 articles were identified after cross-referencing the database searches using the keywords. These revealed that autologous and matrix assisted chondrocyte implantation demonstrated both 'good to excellent' histological results and significant improvement in clinical outcomes. CONCLUSIONS: Autologous and matrix assisted chondrocyte implantation have been shown to treat symptomatic lesions successfully with significant histological and clinical improvement. There is, however, still a need for further randomised clinical trials, perfecting the type of scaffold and the use of adjuncts such as growth factors. A list of recommendations for treatment and the potential future trends of managing these lesions are given.

Estados de ansiedad, depresión y factores relacionados en la población adulta inmigrante latinoamericana en Canarias / Anxiety states, depression and associated factors in the latin american immigrant population in the Canary Islands

Introducción. El acontecimiento vital estresante que supone el fenómeno migratorio puede suponer un factor de mayor riesgo de enfermedad mental. Objetivo. Comparar la prevalencia de ansiedad-depresión en población latinoamericana residente en Canarias con la población autóctona. Material y métodos. Estudio descriptivo-transversal cualitativo y cuantitativo en marzo-agosto de 2009 de los adultos latinoamericanos residentes en Canarias seleccionados en consultas de atención primaria. Encuesta mediante entrevista clínica estructurada y escalas de ansiedad-depresión. Análisis estadístico. Análisis exploratorio de datos y de relación entre variables incluyendo estudio cualitativo de las variables susceptibles. Resultados. Se incluyeron 125 pacientes. Edad media 38,9 años (DE 12,07). El 73,6% eran mujeres, 42,4%casados y el 77,6% tiene empleo. Presentan ansiedad el 44% (IC 95%: 0,527-0,353) y depresión el 63,2% (IC 95%: 0,714-0,546). Un 13,6% refieren haber sufrido malos tratos. Un 19,2% síntomas psicopatológicos infantiles. Un 64,6% tiene antecedentes personales de enfermedad mental. La depresión se asocia al «estado civil» (p=0,012), la «situación familiar» (p<0,0001), el «tiempo en España» (5,75 años ± 3,88 vs 7,50 años ± 7,39; p=0,002) y el «motivo de inmigración» (p=0,050). La ansiedad, con la «edad» (41,1 años ± 12,51 vs 37,2 años ± 11,5; p=0,070) y con el «desempleo» (p=0,014). La ansiedad-depresión con «malos tratos» (76,5 vs 23,5%; p=0,004) (100 vs 0% p=0,001), «síntomas psicopatológicos en infancia» (62,5 vs 37,5%; p=0,042), (83,3 vs 16,7%; p=0,023) y «antecedentes de enfermedad mental» (68,4 vs 31,6%; p<0,001) (84,2 vs 15,8%; p=0,001). Es un factor de riesgo para la ansiedad presentar «antecedentes de salud mental», «sufrir malos tratos» y «no tener trabajo». La depresión se asocia a la «situación familiar» como factor protector y como factor de riesgo «antecedentes de salud mental» y «síntomas psicopatológicos infantiles». El análisis cualitativo ofrece como buenas «relaciones sociales», «visión de la sociedad» y presencia de la «ilusión/esperanza por volver al país». Conclusiones. La prevalencia de ansiedad no es diferente a la de la población general y los factores del hecho migratorio parecen no influir en nuestro estudio (AU)

Introduction. Immigration is a vital stressful event that could be a higher risk of suffering a mental illness. Objective. To compare the prevalence of anxiety-depression in the Latin-American immigrant population living in the Canary Islands and compare them with the non-immigrant population. Material and Method. Exploratory analysis of dates and the relationship between variables, including the qualitative analysis. Results. The study included 125 patients, with a mean age of 38.9 years (SD: 12.07), of whom 73.6% were women, 42.4% married and 77.6% employed. A total of 44% suffered anxiety (95% CI: 0.527-0.353) and 63.2% had depression (95% CI: 0.714-0.546). Abuse was reported by 13.6% and the 19.2% had psychopathological symptoms in childhood. A history of mental illness was reported in 64.6%. Depression was associated with “marital status” (P=.012), “family situation” (P=.0001), “time in Spain” (5.75 years± 3.88 vs. 7.50 years± 7.39 P=.002) and “reason for immigration” (P=.050). Anxiety was associated with “age” (41.1 years± 12.51 vs. 37.2 years± 11.5 P=.070) and “unemployment” (P=.014). Anxiety-depression with “abuses” (76.5 vs. 23.5% P=.004), (100 vs. 0% P=.001), “psychopathological symptoms in childhood” (62.5 vs. 37.5% P=.042), (83.3 vs. 16.7% P=.023) and “clinical history of mental illness” (68.4 vs. 31.6% P=.001), (84.2 vs. 15.8% P=.001). “Clinical history of mental illness”, “abuses” and “unemployment” are risk factors for anxiety. Depression is associated with “family situation” as a protective factor and “clinical history of mental illness” and “psychopathological symptoms in childhood” as a risk factor. The qualitative analysis showed “relationships”, “vision of society” and “hope of going back home” as positive factors. Conclusions. The prevalence of anxiety is no different to the general population, and the migration factors do not appear to modify our study (AU)

Cholesterol degradation by Gordonia cholesterolivorans.

This paper reports physiological and genetic data about the type strain Gordonia cholesterolivorans, a strain that is able to degrade steroid compounds containing a long carbon side chain such as cholesterol (C(27)), cholestenone (C(27)), ergosterol (C(28)), and stigmasterol (C(29)). The length of the carbon side chain appears to be of great importance for this bacterium, as the strain is unable to grow using steroids with a shorter or nonaliphatic carbon side chain such as cholic acid (C(24)), progesterone (C(21)), testosterone, androsterone, 4-androstene-3,17-dione (all C(19)), and further steroids. This study also demonstrates that the degradation of cholesterol is a quite common feature of the genus Gordonia by comparing Gordonia cholesterolivorans with some other species of this genus (e.g., G. sihwensis, G. hydrophobica, G. australis, and G. neofelifaecis). Pyrosequencing of the genome of G. cholesterolivorans led to the identification of two conventional cholesterol oxidase genes on an 8-kb and a 12.8-kb genomic fragment with genetic organizations that are quite unique as compared to the genomes of other cholesterol-degrading bacteria sequenced so far. The identified two putative cholesterol oxidases of G. cholesterolivorans are both intracellularly acting enzymes of the class I type. Whereas one of these two cholesterol oxidases (ChoOx-1) shows high identity with an oxidoreductase of the opportunistic pathogen G. bronchialis and is not transcribed during growth with cholesterol, the other one (ChoOx-2) appears phylogenetically closer to cholesterol oxidases from members of the genus Rhodococcus and is transcribed constitutively. By using targeted gene disruption, a G. cholesterolivorans ChoOx-2 gene mutant strain that was unable to grow with steroids was obtained.