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Metastasis is an intricate and formidable pathophysiological process encompassing the dissemination of cancer cells from the primary tumour body to distant organs. It stands as a profound and devastating phenomenon that constitutes the primary driver of cancer-related mortality. Despite great strides of advancements in cancer research and treatment, tailored anti-metastasis therapies are either lacking or have shown limited success, necessitating a deeper understanding of the intrinsic elements driving cancer invasiveness. This comprehensive review presents a contemporary elucidation of pivotal facets within the realm of cancer metastasis, commencing with the intricate processes of homing and invasion. The process of angiogenesis, which supports tumour growth and metastasis, is addressed, along with the pre-metastatic niche, wherein the primary tumour prepares for a favorable microenvironment at distant sites for subsequent metastatic colonization. The landscape of metastasis-related genetic and epigenetic mechanisms, involvement of metastasis genes and metastasis suppressor genes, and microRNAs (miRNA) are also discussed. Furthermore, immune modulators' impact on metastasis and their potential as therapeutic targets are addressed. The interplay between cancer cells and the immune system, including immune evasion mechanisms employed by metastatic cells, is discussed, highlighting the importance of targeting immune modulation in arresting metastatic progression. Finally, this review presents promising treatment opportunities derived from the insights gained into the mechanisms of metastasis. Identifying novel therapeutic targets and developing innovative strategies to disrupt the metastatic cascade holds excellent potential for improving patient outcomes and ultimately reducing cancer-related mortality.
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OBJECTIVE: Vasomotor symptoms (VMS) due to menopause cause substantial burden and distress. Some women join online communities to share experiences and treatment outcomes through peer-to-peer interactions. This study describes women's experiences with VMS and symptom management on the PatientsLikeMe online support group. METHODS: Mixed-methods research included women aged 40 to 65 years in the PatientsLikeMe community who were recruited using convenience sampling. Text from online posts by members was analyzed retrospectively using natural language processing. Relevant data, including numbers and percentages of women and frequencies of mentions, were summarized descriptively. Qualitative semistructured interviews were conducted; data, notes, and recordings were transcribed and deidentified and thematic analyses were performed. RESULTS: Demographic information was available from 1,614 accounts included in retrospective text analyses. Women had a mean age of 56.7 years; most were White (87.8%) and not Hispanic/Latino (90.2%). Hot flashes and night sweats were most commonly mentioned symptoms (n = 146). Of 16 women who were interviewed, 14 met the inclusion criteria, and their responses were included in the analysis. VMS impacted life quality in terms of physical (43%) and mental well-being (36%), social activities (21%), and productivity (14%). Symptom management included temperature regulation (43%), lifestyle changes (36%), over-the-counter Estroven (29%), hormone therapy (21%), and contraceptives (21%). Half of the women were surprised by symptom intensity and duration; many felt unheard by their healthcare providers. CONCLUSIONS: VMS have a substantial negative impact on multiple aspects of women's life. Management strategies for these symptoms vary widely, and many women feel unprepared for navigating the complex challenges of menopause.
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Sofocos , Menopausia , Investigación Cualitativa , Sudoración , Humanos , Femenino , Persona de Mediana Edad , Sofocos/terapia , Menopausia/fisiología , Menopausia/psicología , Estudios Retrospectivos , Adulto , Anciano , Sistema Vasomotor/fisiopatología , Calidad de VidaRESUMEN
Due to the fact that the existing generation of wireless communication cannot possibly keep up with the current traffic explosion and emerging applications, research and development on next-generation (i.e., sixth generation, 6G) wireless technologies is being carried out worldwide. In this regard, it is anticipated that the space-air-ground (SAG) network with free space optics (FSO) communication can provide the terabits per second throughput necessary to sustain various potential 6G applications. However, FSO communications are susceptible to atmospheric turbulence, pointing errors, and beam scintillation effects. To remedy the severe atmospheric effects, we propose a multiple high-altitude platform station (HAPS)-based SAG network with a HAPS selection scheme. For the proposed system, we have derived the closed-form expressions for outage probability, average symbol error rate (SER), ergodic capacity, and outage capacity over Málaga distribution with pointing errors. Further, the asymptotic expressions for outage probability, average SER, and outage capacity were derived to enhance the comprehension of the system from a practical standpoint. It is observed from the numerical results that the multiple HAPS-based FSO system performs better than the existing HAPS-based FSO systems.
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AIM: To identify the genetic etiology of neonatal diabetes in an infant and to elucidate the molecular mechanism of the identified mutation underlying the pathogenesis. METHODS: Genetic analysis was carried out by sequencing of known etiological genes associated with NDM. Molecular characterization was performed by constructing a identified mutation in NKX2-2 gene and functional aspects was tested using transactivation, protein expression, DNA binding, nuclear localization assays. Structural analysis was performed by modeling the NKX2-2 protein structure. RESULTS: A novel homozygous frameshift mutation c.772delC, p.Q258SFs*59 in the NKX2-2 gene was identified in a patient with neonatal diabetes. Functional studies revealed that this mutation resulted in an elongated protein sequence, affecting DNA binding activity and transcriptional function. Structural analysis suggested alterations in the protein's tertiary structure, likely contributing to its dysfunction. CONCLUSION: This study presents the first report of a stop-loss mutation in the NKX2-2 gene associated with NDM. Our findings emphasize the importance of functional and structural characterization to understand the biological consequences of such mutations. This comprehensive analysis provides insights into the molecular mechanisms underlying NDM and its clinical phenotype, which may aid in better diagnosis and management of patients with similar variants in the future.
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Diabetes Mellitus , Enfermedades del Recién Nacido , Recién Nacido , Lactante , Humanos , Factores de Transcripción/genética , Diabetes Mellitus/genética , Mutación , Mutación del Sistema de Lectura , Enfermedades del Recién Nacido/genética , ADNRESUMEN
Long non-coding RNAs (lncRNAs) have emerged as auxiliary regulators of gene expression influencing tumor microenvironment, metastasis and radio-resistance in cancer. The presence of lncRNA in extracellular fluids makes them promising diagnostic markers. LncRNAs deploy higher-order structures to facilitate a complex range of functions. Among such structures, G-quadruplexes (G4s) can be detected or targeted by small molecular probes to drive theranostic applications. The in vitro identification of G4 formation in lncRNAs can be a tedious and expensive proposition. Bioinformatics-driven strategies can provide comprehensive and economic alternatives in conjunction with suitable experimental validation. We propose a pipeline to identify G4-forming sequences, protein partners and biological functions associated with dysregulated lncRNAs in cervical cancer. We identified 17 lncRNA clusters which possess transcripts that can fold into a G4 structure. We confirmed in vitro G4 formation in the four biologically active isoforms of SNHG20, MEG3, CRNDE and LINP1 by Circular Dichroism spectroscopy and Thioflavin-T-assisted fluorescence spectroscopy and reverse-transcriptase stop assay. Gene expression data demonstrated that these four lncRNAs can be potential prognostic biomarkers of cervical cancer. Two approaches were employed for identifying G4 specific protein partners for these lncRNAs and FMR2 was a potential interacting partner for all four clusters. We report a detailed investigation of G4 formation in lncRNAs that are dysregulated in cervical cancer. LncRNAs MEG3, CRNDE, LINP1 and SNHG20 are shown to influence cervical cancer progression and we report G4 specific protein partners for these lncRNAs. The protein partners and G4s predicted in lncRNAs can be exploited for theranostic objectives.
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ARN Largo no Codificante , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/genética , ARN Largo no Codificante/genética , Bioensayo , Biología Computacional , Líquido Extracelular , Microambiente TumoralRESUMEN
BACKGROUND: Major depressive disorder (MDD) is a recurrent psychiatric condition that presents challenges in responding to treatment and achieving long-term remission. To improve outcomes, a shared decision-making treatment approach with patient and healthcare practitioner (HCP) engagement is vital. PatientsLikeMe (PLM), a peer community of patients, provides information on MDD, symptoms, and treatment through forums and resources, helping patients stay engaged in their treatment journey. Data on PLM can be harnessed to gain insights into patient perspectives on MDD symptom management, medication switches, and treatment goals and measures. METHODS: This ongoing, decentralized, longitudinal, observational, prospective study is being conducted using the PLM platform in two parts, enrolling up to 500 patients with MDD in the United States aged ≥ 18 years to compare vortioxetine with other monotherapy antidepressants. The first qualitative component consists of a webinar and discussion forum with PLM community members with MDD, followed by a pilot for functionality testing to improve the study flow and questions in the quantitative survey. The quantitative component follows on the PLM platform, utilizing patient-reported assessments, over a 24-week period. Three surveys will be conducted at baseline and weeks 12 and 24 to collect data on patient global impression of improvement, depression severity, cognitive function, quality of life (QoL) and well-being, medication satisfaction, emotional blunting, symptoms of anhedonia and resilience, as well as goal attainment. Quantitative results will be compared between groups. The qualitative component is complete; patient recruitment is underway for the quantitative component, with results expected in late 2023. DISCUSSION: These results will help HCPs understand patient perspectives on the effectiveness of vortioxetine versus other monotherapy antidepressants in alleviating symptoms of MDD and improvements in QoL. Data from the PLM platform will support a patient goal-based treatment approach, as results can be shared by patients with their HCPs, providing them with insights on patient-centric goals, treatment management and adherence, as well as allowing them to observe changes in patient-related outcomes scores. Findings from the study will also help to optimize the PLM platform to build scalable solutions and connectivity within the community to better serve patients with MDD.
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Trastorno Depresivo Mayor , Humanos , Vortioxetina/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/diagnóstico , Estudios Prospectivos , Calidad de Vida , Nivel de Atención , AntidepresivosRESUMEN
Breast cancer is one of the most prevalent cancers in women and a leading cause of mortality. As per the GLOBCAN report of 2021, breast cancer has surpassed lung cancer which until recently was the most commonly diagnosed cancer. Despite significant efforts to improve early detection and therapeutic efficacy of breast cancer, the frequent emergence of drug resistance remains the predominant basis for the poor prognosis of cancer patients harboring various malignancies. Long non-coding RNA (lncRNAs) are known to affect a variety of components of genome function, including epigenetics, gene transcription, splicing, translation, as well as many central biological processes like cell cycle progression, cell differentiation, development, and pluripotency. LncRNAs are dysregulated in various malignancies and interact with a multitude of RNAs and proteins to impact drug resistance. LncRNAs regulate chemoresistance in cancer by employing an assortment of molecular mechanisms including multidrug efflux, suppression of apoptosis, DNA damage response, epigenetic alterations, as well as functioning as competitive endogenous RNA. When combined with other regulatory mechanisms, these pathways form a complex orchestration of signaling that ultimately lead to chemoresistance. The current review delves into the role of lncRNAs in inducing drug resistance to conventional therapeutic anti-cancer drugs used for the treatment of breast cancer. We propose that lncRNAs that provoke drug resistance could be used to develop new targeted and tailored therapeutics providing a novel approach to introduce promising personalized treatment modalities to overcome chemoresistance in breast cancer patients. Hence, lncRNAs that drive anticancer drug resistance can be potentially explored as biomarkers of disease prognosis and may provide unique opportunities to circumvent chemoresistance in breast cancer patients.
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Antineoplásicos , Neoplasias de la Mama , Neoplasias Pulmonares , ARN Largo no Codificante , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Parotid gland tuberculosis is a very rare form of extrapulmonary tuberculosis, with less than 200 cases reported in literature. We describe a 10-year-old female who presented with a swelling in the left parotid region during the last month. CT scan neck revealed an abscess in the left parotid gland extending into the submandibular gland, muscles, and bone. Pus aspirated by FNAC showed acid fast bacilli in the ZN stain, and GeneXpert was positive for rifampicin-sensitive Mycobacterium tuberculosis. She was successfully treated with antituberculous therapy given for 6 months. Parotid gland tuberculosis, although rare, has a good prognosis with drug therapy. Surgery is rarely required.
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Trimethoprim, a preferred treatment for urinary tract infections, is becoming obsolete owing to the rapid dissemination of resistant E. coli. Although direct resistance mechanisms such as overexpression of a mutant FolA and dfr enzymes are well characterized, associated alterations that drive or sustain resistance are unknown. We identify the repertoire of resistance-associated perturbations by constructing and interrogating a transcriptome-integrated functional interactome. From the cross talk between perturbations in stress-response and metabolic pathways, we identify the critical dependence on serine hydroxymethyltransferase (GlyA) as an emergent vulnerability. Through its deletion, we demonstrate that GlyA is necessary to sustain high levels of resistance in both laboratory-evolved resistant E. coli and a multidrug-resistant clinical isolate. Through comparative evolution, we show that the absence of GlyA activity decelerates the acquisition of resistance in E. coli. Put together, our results identify GlyA as a promising target, providing a basis for the rational design of drug combinations.
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The gap in access to maternal health care services is a challenge of an unequal world. In 2015, each day about 830 women died due to complications of pregnancy and childbirth. Almost all of these deaths occurred in low-resource settings, and most could have been prevented. This study quantified the contributions of the socioeconomic determinants of inequality to the utilization of maternal health care services in four countries in diverse geographical and cultural settings: Bangladesh, Ethiopia, Nepal and Zimbabwe. Data from the 2010-11 Demographic and Health Surveys of the four countries were used, and methods developed by Wagstaff and colleagues for decomposing socioeconomic inequalities in health were applied. The results showed that although the Concentration Index (CI) was negative for the selected indicators, meaning maternal health care was poorer among lower socioeconomic status groups, the level of CI varied across the different countries for the same outcome indicator: CI of -0.1147, -0.1146, -0.2859 and -0.0638 for <3 antenatal care visits; CI of -0.1338, -0.0925, -0.1960 and -0.2531 for non-institutional delivery; and CI of -0.1153, -0.0370, -0.1817 and -0.0577 for no postnatal care within 2 days of delivery for Bangladesh, Ethiopia, Nepal and Zimbabwe, respectively. The marginal effects suggested that the strength of the association between the outcome and explanatory factors varied across the different countries. Decomposition estimates revealed that the key contributing factors for socioeconomic inequalities in maternal health care varied across the selected countries. The findings are significant for a global understanding of the various determinants of maternal health care use in high-maternal-mortality settings in different geographical and socio-cultural contexts.
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Comparación Transcultural , Servicios de Salud Materna/estadística & datos numéricos , Clase Social , Factores Socioeconómicos , Revisión de Utilización de Recursos/estadística & datos numéricos , Adolescente , Adulto , África del Sur del Sahara , Asia , Parto Obstétrico/estadística & datos numéricos , Femenino , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Atención Posnatal/estadística & datos numéricos , Embarazo , Atención Prenatal/estadística & datos numéricos , Adulto JovenRESUMEN
RHF and DFT calculations were carried out to study the optimized molecular geometries and vibrational characteristics of the 4,5-ethylenedithio-1,3-dithiole-2-thione (EDT-DTT) and 4,5-ethylenedithio-1,3-dithiole-2-one (EDT-DTO) molecules and their radical cations and anions. It is found that the anionic radical of the EDT-DTO molecule is unstable. Both the neutral molecules and their radical cations have non-planar structures with C(2) symmetry while the radical anion of the EDT-DTT molecule has non-planar structure with C(1) symmetry. It is found that the most of the vibrational characteristics of the radicals are similar to their corresponding neutral molecules, however, for some of the modes significant changes are noticed. As a result of anionic radicalization of EDT-DTT, the IR intensity and Raman activity increase and Raman band becomes polarized for both the CH(2) twisting modes. Drastic enhancements in the Raman activity and reduced IR intensity are noticed for the C=S/O stretching mode in going from neutral molecules to their radical ions consistent with charge separation along this bond. The C=S and C=C stretching wavenumber changes are consistent with corresponding bond length changes in going from neutral to their radical ions.