Targeting LINC00665/miR-199b-5p/SERPINE1 axis to inhibit trastuzumab resistance and tumorigenesis of gastric cancer via PI3K/AKt pathway.

Long noncoding RNAs (lncRNAs) serve as critical mediators of tumor progression and drug resistance in cancer. Herein, we identified a lncRNA, LINC00665, associated with trastuzumab resistance and development in gastric cancer (GC). LINC00665 was highly expressed in GC tissues and high expression of LINC00665 was correlated with poor prognosis. LINC00665 knockdown was verified to suppress migration, invasion, and resistance to trastuzumab in GC. Furthermore, we found that LINC00665 participates in the infiltration of naive B cells, mast cells, and T follicular helper (Tfh) cells. Mechanistically, LINC00665 was confirmed to regulate tumorigenesis and trastuzumab resistance by activating PI3K/AKt pathway. LINC00665 sponged miR-199b-5p to interact with SERPINE1 expression, resulting in the increase of phosphorylation of AKt, thus participating in the PI3K/AKt pathway. To summarize, LINC00665 facilitated the tumorigenesis and trastuzumab resistance of GC by sponging miR-199b-5p and promoting SERPINE1 expression, which further activated PI3K/AKt signaling; this finding reveals a new mechanism by which LINC00665 modulates tumor development and drug resistance in GC.

MiR-204-5p overexpression abrogates Dacarbazine-induced senescence in melanoma cells in vivo MiR-204-5p abrogates senescence.

Cancer cell drug resistance hinders significantly therapeutic modalities in oncology. Dacarbazine is chemotherapeutic agent traditionally used for melanoma treatment although it's effectiveness insufficient. In the present study we performed NGS-based transcriptomic profiling of B16 melanoma tumors after Dacarbazine treatment in vivo. Whole transcriptome sequencing revealed 34 differentially expressed genes most of them associated with drug resistance and apoptosis evading. In accordance to bionformatic analysis, 6 signaling cascades: "D-Amino acid metabolism", "NF-kappa B signaling pathway", "Phosphatidylinositol signaling system", "P53 signaling pathway", "IL-17 signaling pathway" and "Bile secretion" were enriched by differentially expressed genes. Next we provided a combined treatment by Dacarbazine and miR-204-5p mimic as miR-204-5p was considered previously implicated in cancer drug resistance. This approach lead to an increase of miR-204-5p expression in B16 melanoma cells in vivo that was accompanied by subsequent decrease in the expression of miR-204-5p target genes - BCL2 and SIRT1 in the primary tumors. MiR-204-5p overexpression with Dacarbazine application resulted in increased the weight, and volume of primary tumors and diminished the proportion of ß-Galactosidase expression in melanoma B16-bearing mice. Taking together, our study revealed that although miR-204-5p showed antiproliferative capacities in vitro, it's mimic in combination with Dacarbazine is able to potentiate tumor growth triggering probably a switch from senescent to proliferative phenotype of malignant cells.

Características del almacenamiento de antibióticos en una población suburbana de México

Objetivo: Determinar las características de almacenamiento de los antibióticos de las familias en una población suburbana en México. Metodología: El enfoque del estudio es cuantitativo, observacional, de corte transversal y alcance descriptivo. La unidad de estudio fueron las familias que vivían en el área de estudio de una zona suburbana en México. Resultados: Se encuestaron un total de 235 familias, dentro de las cuales existen diversos grupos etarios, de los cuales predominaron las edades de entre 36 a 64 años en 153 familias. Se obtuvo que más del 70 % presentaban enfermedades y, respecto a la posibilidad de que tuviesen almacenados medicamentos antibióticos caducados o próximos a caducar, el 68.1 % mencionó que no era probable. Conclusiones: El importante número de población adulta, la amplia presencia de comorbilidades y diversos factores sociodemográficos impactan en las prácticas y actitudes en relación con las formas en que las familias obtienen, usan, almacenan y desechan los medicamentos dentro de sus hogares. Esta investigación busca contribuir a la concientización y creación de diversos programas para la adopción de medidas de seguridad para el almacenamiento de medicamentos dentro del hogar, así como servir de guía en la identificación de procedimientos óptimos, eficientes y eficaces para tratar este fenómeno.

Objetivo: Determinar as características do armazenamento de antibióticos das famílias em uma população suburbana no México. Metodologia: A abordagem do estudo é quantitativa, observacional, transversal e de escopo descritivo. A unidade de estudo foram as famílias que viviam na área de estudo de uma zona suburbana no México. Resultados: Foram pesquisadas 235 famílias, de diversas faixas etárias, das quais predominaram as idades de 36 a 64 anos em 153 famílias. Verificou-se que mais de 70% apresentavam enfermidades, e com relação à possibilidade de terem medicamentos antibióticos vencidos ou prestes a vencer armazenados, 68,1 % mencionaram que não era provável. Conclusões: O significativo número de população adulta, a ampla presença de comorbidades e vários fatores sociodemográficos impactam nas práticas e atitudes relativas às formas como as famílias obtêm, usam, armazenam e descartam medicamentos em suas residências. Esta pesquisa busca contribuir para a conscientização e a criação de vários programas para a adoção de medidas de segurança para o armazenamento de medicamentos em casa, bem como servir de guia na identificação de procedimentos ideais, eficientes e eficazes para lidar com esse fenômeno.

Objective: To determine the antibiotic storage characteristics of families in a suburban population in Mexico. Methodology: The study approach is quantitative, observational, cross-sectional and descriptive in scope. The unit of study was families living in the area under study in a suburban zone of Mexico. Results: A total of 235 families were surveyed, within which there are different age groups, with 153 families predominantly aged between 36 and 64 years old. It was obtained that more than 70 % presented illnesses and, regarding the possibility that they had stored expired or soon to expire antibiotic drugs, 68.1 % mentioned that it was not likely. Conclusions: The significant number of adult population, the wide presence of comorbidities and various sociodemographic factors impact practices and attitudes regarding the ways in which families obtain, use, store and dispose of medications within their homes. This research seeks to contribute to the awareness and creation of various programs for the adoption of safety measures for the storage of medicines within the home, as well as to serve as a guide in the identification of optimal, efficient and effective procedures to deal with this phenomenon.

Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia.

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

Impact of heteroresistance on treatment outcomes of people with drug-resistant TB.

BACKGROUND: Poor treatment outcomes among people with drug-resistant TB (DR-TB) are a major concern. Heteroresistance (presence of susceptible and resistant Mycobacterium tuberculosis in the same sample) has been identified in some people with TB, but its impact on treatment outcomes is unknown. METHODS: We used targeted deep sequencing to identify mutations associated with DR-TB and heteroresistance in culture samples of 624 people with DR-TB. We evaluated the association between heteroresistance and time to unfavorable treatment outcome using Cox proportional hazards regression. RESULTS: The proportion of drug-resistant isolates with a known mutation conferring resistance was lower for streptomycin (45.2%) and second-line injectables (79.1%) than for fluoroquinolones (86.7%), isoniazid (93.2%) and rifampin (96.5%). Fifty-two (8.3%) had heteroresistance, and it was more common for fluoroquinolones (4.6%) than rifampin (2.2%), second-line injectables (1.4%), streptomycin (1.7%), or isoniazid (1.3%). There was no association between heteroresistance and time to unfavorable outcome among people with multidrug-resistant TB (adjusted hazard ratio [aHR] 1.74, 95% CI 0.39-7.72) or pre-extensively DR-TB (aHR 0.65, 95% CI 0.24-1.72). CONCLUSIONS: Heteroresistance was relatively common (8.3%) among people with DR-TB in the Philippines. However, we found insufficient evidence to demonstrate an impact on unfavorable treatment outcomes.

CONTEXTE: Les résultats médiocres du traitement chez les personnes atteintes de TB résistante aux médicaments (DR-TB, pour l'anglais « drug-resistant TB ¼) constituent une préoccupation significative. L'hétérorésistance, caractérisée par la coexistence de souches sensibles et résistantes de Mycobacterium tuberculosis dans un même échantillon, a été observée chez certains patients, mais les conséquences de cette situation sur l'efficacité des traitements demeurent incertaines. MÉTHODES: Nous avons recouru au séquençage profond ciblé afin d'identifier les mutations liées à la DR-TB et à l'hétérorésistance dans les échantillons de culture provenant de 624 personnes atteintes de DR-TB. Nous avons analysé le lien entre l'hétérorésistance et le délai jusqu'à l'issue défavorable du traitement en utilisant une régression des risques proportionnels de Cox. RÉSULTATS: La proportion d'isolats, présentant une mutation connue associée à la résistance, était inférieure pour la streptomycine (45,2%) et les médicaments injectables de deuxième ligne (79,1%) par rapport aux fluoroquinolones (86,7%), à l'isoniazide (93,2%) et à la rifampicine (96,5%). Parmi les isolats, cinquante-deux (8,3%) manifestaient une hétérorésistance, plus courante pour les fluoroquinolones (4,6%) que pour la rifampicine (2,2%), les médicaments injectables de deuxième ligne (1,4%), la streptomycine (1,7%) ou l'isoniazide (1,3%). Aucune association n'a été observée entre l'hétérorésistance et un délai d'évolution défavorable chez les patients atteints de TB multirésistante (rapport de risque ajusté [aHR] 1,74 ; IC à 95% 0,39­7,72) ou de DR-TB pré-extensive (aHR 0,65 ; IC à 95% 0,24­1,72). CONCLUSIONS: L'hétérorésistance a été observée de manière relativement fréquente (8,3%) chez les personnes atteintes de DR-TB aux Philippines. Néanmoins, nous n'avons pas identifié de preuves suffisantes pour établir un lien avec des résultats de traitement défavorables.

[Reevaluation of penicillin allergy labeling, appropriate use of ß-lactam antibiotics, and multidrug resistance]. / Reevaluación del rótulo de alergia a penicilina, el uso adecuado de antibióticos ß-lactámicos y la multirresistencia.

Approximately 10% of the population reports being allergic to penicillin, although usually less than 1% really are. In addition, people with proven allergies over the years may no longer be allergic. Unconfirmed penicillin allergy and use of alternative antimicrobials result in more treatment failures; more severe adverse effects. Higher cost; longer hospitalizations; increase in the emergence of multi-resistant germs associated with health care. The risk of cross-allergy between ß-lactam groups is usually <2%, depending on the similarity of the side chains, so prescribing antibiotics from another ß-lactam group is safe as long as we take into account the structural similarity. Incorporating the reassessment of allergies and improving the prescription of antibiotics in this group of patients reduces the generation and spread of multi-resistant germs, and the associated costs. There are simple methods and specific scores that simplify allergy reassessment. The objective of this review is to expose how, through these methods, the delabeling of patients erroneously labeled as allergic and the safe prescription of ß-lactam antibiotics can be achieved.

Aproximadamente el 10% de la población refiere ser alérgico a la penicilina, aunque habitualmente menos del 1% lo es; además las personas con alergia demostrada con el paso de los años pueden dejar de ser alérgicos. La alergia a la penicilina sin confirmación y el uso de antimicrobianos alternativos tienen como efecto más fallas en el tratamiento; más efectos adversos graves; mayor costo; internaciones más prolongadas; incremento en la emergencia de gérmenes multirresistentes asociados a los cuidados de la salud. El riesgo de alergia cruzada entre grupos de ß-lactámicos suele ser <2%, dependiendo de la similitud de las cadenas laterales, por lo que prescribir antibióticos de otro grupo de ß-lactámicos es seguro siempre que tengamos en cuenta la similitud estructural. Incorporar la reevaluación de alergias y mejorar la prescripción de antibióticos en este grupo de pacientes, disminuye la generación y propagación de gérmenes multirresistentes, y los costos asociados. Existen métodos sencillos y escalas específicas que permiten simplificar la reevaluación de la alergia. El objetivo de esta revisión es exponer cómo a través de estos métodos, puede lograrse el desrotulado de pacientes erróneamente etiquetados como alérgicos y la prescripción segura de antibióticos ß-lactámicos.

Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy.

KS18, a Mcl-1 inhibitor, improves the effectiveness of bortezomib and overcomes resistance in refractory multiple myeloma by triggering intrinsic apoptosis.

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and almost all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive" which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates that KS18 effectively induces cell death in MM by dual regulatory mechanisms targeting the Mcl-1 protein at both transcriptional and post-translational levels. Specifically, KS18 suppresses Mcl-1 activation via STAT-3 pathway and promotes Mcl-1 phosphorylation/ubiquitination/proteasome-dependent protein degradation (UPS). Significantly, KS18 triggered caspase-dependent apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. KS18 promises to overcome bortezomib and venetoclax resistance and re-sensitize myeloma cells to chemotherapy. Furthermore, the study shows the tremendous impact of KS18 in inhibiting colony formation in bortezomib-resistant cells and demonstrates significant tumor shrinkage in KS18-treated NSG mice without notable toxicity signs after 4 weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance.

Distinct Clusters of HIV-1 CRF01_AE in Zhejiang, China: High-Risk Transmission Cluster 4 Requires Heightened Surveillance.

Background: HIV-1 CRF01_AE is becoming the predominant HIV-1 subtype among patients in China. The distribution and characteristics of transmission clusters of HIV-1 CRF01_AE in Zhejiang, Eastern China remains unclear. This study analyzed the epidemiologic characteristics and transmission clusters of HIV-1 CRF01_AE in Zhejiang. Methods: Plasma samples obtained from 152 patients of HIV-1 CRF01_AE not undergoing ART were used to amplify HIV-1 pol and env gene. CRF01_AE drug resistance mutations (DRM) prevalence was analysed using Stanford University's HIV Drug Resistance Database. A phylogenetic tree was constructed using FastTree (version 2.1.11) based on the GTR nucleotide substitution model and visualized using Figtree (version 1.4.4) and The Interactive Tree of Life; the Chinese HIV Gene Sequence Data Platform was used to construct genetic transmission networks. Results: Majority samples could be grouped into CRF01_AE transmission Clusters 1 (11.2%), 4 (64.5%), and 5 (7.2%). The CD4+ T-cell counts in Cluster 1, 4a, 4b are lower than 5 were 15, 38, 30, and 248 cells/mm3, respectively (P < 0.05). The high X4 tropism rates were 13.2%, 11.8%, 20.0%, and 0.0% in Clusters 1, 4a, 4b, and 5, respectively. DRM rates in Clusters 4a and 4b were 17.6%, and 25.45% respectively (P < 0.05), whereas they were 17.6% and 18.2% in Clusters 1 and 5, respectively. In total, 24 transmission genetic networks, comprising 72 sequences and 61 links, were discovered; of them, 61.2%, 11.7%, and 18.2% were from Clusters 4, 1, and 5, respectively (P < 0.05). Conclusion: In Zhejiang, different CRF01_AE clusters displayed unique clinic features. Cluster 4, particularly Cluster 4b, was considered a high-risk transmission cluster. The surveillance of epidemiology of HIV-1 should be enhanced to minimize its transmission.

Mechanism of Drug Resistance to First-Line Chemotherapeutics Mediated by TXNDC17 in Neuroblastomas.

BACKGROUND: The prognosis of high-risk neuroblastomas (NB) that are resistant to first-line induction chemotherapy is relatively poor. This study explored the mechanism of resistance to first-line chemotherapeutics mediated by TXNDC17 and its potential solutions in NB. METHODS: The genetic and clinical data of patients with NB were obtained from the Therapeutically Applicable Research to Generate Effective Treatments dataset. TXNDC17 and BECN1 expressions in NB cells were up- and downregulated by transfection with plasmids and shRNA, respectively. Autophagy-related proteins were detected by western blot. Cell viability was determined using cell proliferation and toxicity experiments. Apoptotic cells were detected using flow cytometry. RESULTS: Overall, 1076 pediatric and adolescent patients with NB were enrolled in this study. The 10-year overall survival (OS) rates and event-free survival (EFS) rates for the patients with a mutation of BECN1 were 37.4 ± 9.1% and 34.5 ± 8.8%, respectively. For patients with a mutation of TXNDC17, the 10-year OS and EFS were 41.4 ± 5.9% and 24.3 ± 5.1%, respectively, which were significantly lower than those in the unaltered group. The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance. CONCLUSIONS: Acquired resistance to first-line chemotherapeutics was associated with autophagy mediated by BECN1 and regulated by TXNDC17, which can be reversed by SAHA.

KHDRBS3 facilitates self-renewal and temozolomide resistance of glioblastoma cell lines.

Glioblastoma is a deadly tumor which possesses glioblastoma stem cell populations involved in temozolomide (TMZ) resistance. To gain insight into the mechanisms of self-renewing and therapy-resistant cancer stem cells, subcellular proteomics was utilized to identify proteins whose expression is enriched in U251-derived glioblastoma stem-like cells. The KH RNA Binding Domain Containing, Signal Transduction Associated 3, KHDRBS3, was successfully identified as a gene up-regulated in the cancer stem cell population compared with its differentiated derivatives. Depletion of KHDRBS3 by RNA silencing led to a decrease in cell proliferation, neurosphere formation, migration, and expression of genes involved in glioblastoma stemness. Importantly, TMZ sensitivity can be induced by the gene knockdown. Collectively, our results highlight KHDRBS3 as a novel factor associated with self-renewal of glioblastoma stem-like cells and TMZ resistance. As a consequence, targeting KHDRBS3 may help eradicate glioblastoma stem-like cells.

Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review).

Lenvatinib (LEN) is a multi-target TKI, which plays a pivotal role in the treatment of advanced hepatocellular carcinoma (HCC). The inevitable occurrence of drug resistance still prevents curative potential and is deleterious for the prognosis, and a growing body of studies is accumulating, which have devoted themselves to unveiling its underlying resistance mechanism and made some progress. The dysregulation of crucial signaling pathways, non-coding RNA and RNA modifications were proven to be associated with LEN resistance. A range of drugs were found to influence LEN therapeutic efficacy. In addition, the superiority of LEN combination therapy has been shown to potentially overcome the limitations of LEN monotherapy in a series of research, and a range of promising indicators for predicting treatment response and prognosis have been discovered in recent years. In this review, we summarize the latest developments in LEN resistance, the efficacy and safety of LEN combination therapy as well as associated indicators, which may provide new insight into its resistance as well as ideas in the treatment of advanced HCC.

Receptor tyrosine kinases in breast cancer treatment: unraveling the potential.

Breast cancer is a multifactorial disease driven by acquired genetic and epigenetic changes that lead to aberrant regulation of cellular signaling pathways. Receptor tyrosine kinases (RTKs), a class of critical receptors, are involved in the initiation and progression of breast cancer. RTKs are cell surface receptors with unique structures and biological characteristics, which respond to environmental signals by initiating signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway, Janus kinase (JAK)/signal transducer, activator of transcription (STAT) pathway, and phosphoinositide 3-kinase (PI3K)/AKT pathway. The critical role of RTKs makes them suitable targets for breast cancer treatment. Targeted therapies against RTKs have been developed in recent years, evaluated in clinical trials, and approved for several cancer types, including breast cancer. However, breast cancer displays molecular heterogeneity and exhibits different therapeutic responses to various drug types, leading to limited effectiveness of targeted therapy against RTKs. In this review, we summarize the structural and functional characteristics of selected RTKs and discuss the mechanisms and current status of drug therapy involving different protein tyrosine kinases in breast cancer progression.

Utidelone-based therapy in advanced or metastatic solid tumors after failure of standard therapies: a prospective, multicenter, single-arm trial.

Treatment options are limited for tumors after failure of standard therapies. Utidelone (UTD1), a novel microtubule stabilizer, given via 5 days intermittent infusion, has demonstrated high activity in heavily pretreated metastatic breast cancer, while its efficacy in other cancers was unclear. Peripheral neuropathy is a common and severe adverse event (AE) of UTD1. We performed a prospective, multicenter, single-arm trial (ChiCTR2300074299) to evaluate the efficacy and safety of UTD1 with a changed administration mode in patients with advanced or metastatic solid tumors after failure of standard therapies. UTD1 (150 mg/m2, alone or in combination with other anticancer agents) was administrated via 120 h continuous intravenous infusion every 21 days until disease progression or intolerable toxicity. A total of 50 patients were enrolled and analyzed, including 20 breast cancer patients, 11 gynecological cancer patients, 8 gastrointestinal cancer patients, 6 lung cancer patients, and 5 patients with other solid tumors. The overall median progression-free survival (PFS) was 4 months, the overall objective response rate and disease control rate were 20% and 66%, respectively, and the median overall survival was not reached. Most of the AEs were grade 1 or 2 and were manageable and reversible, the rate of grade ≥3 AEs including peripheral neuropathy was 4%. This study demonstrated a promising anti-tumor activity of UTD1 in patients with advanced or metastatic solid tumors after failure of the standard therapies. Moreover, 120 h continuous intravenous infusion was a more tolerable administration mode than 5 days intermittent infusion, and worthy of further study.

Systematic review on buparvaquone resistance associated with non-synonymous mutation in drug binding genes site of Theileria annulate.

Theileria annulata (T. annulata) is intra-erythrocytic protozoan parasite which is more prevalent in tropical and sub-tropical countries. It has a significant economic impact on the productivity of the dairy industry, and buparvaquone is used to treat infected animals in the prevalent regions of the world. Systematically, buparvaquone targets the cyto-b gene to break the electron transport chain (ETC) and Theileria annulata peptidyl-prolyl isomerase 1 (TaPIN1) gene to destabilize transcription factor JUN (c-JUN) to inhibit proliferation of infected cells, which ultimately leads to the death of T. annulata. The reported studies on drug resistance is due to inappropriate drug application, evolutionary characteristics of the cytochrome b (cyto-b) gene and oncogenic signaling pathways gene (TaPIN1) make the parasite resistant against buparvaquone. Hence, this systematic review was designed to find out non-synonymous mutation in genes (cyto-b and TaPIN1) responsible for drug resistance reported from Tunisia, Turkey, Egypt, Sudan, Iran, Pakistan, China and Germany with reference to the T. annulata Ankara strain of cyto-b (accession no. XM_949625.1) and TaPIN1 (accession no. TA18945) wild type genes. Non-synonymous point mutations were found in cyto-b (Q01 at 130-148 and Q02 at 253-262 regions) and TaPIN1 (A53P and A53T) genes. These point mutations are responsible for developing buparvaquone resistance against T. annulata infection. These genes can be used as biomarkers for the identification of drug resistance in any endemic area. To avoid the complication of drug resistance, development of genetically resistant cattle breeds, potent vaccines and anti-theilerial drugs (Trifloxystrobin and anti-cancerous) are currently required to control proliferating economically important T. annulata parasites.

MicroRNA signatures in osteosarcoma: diagnostic insights and therapeutic prospects.

Osteosarcoma (OSa) is the most prevalent primary malignant bone tumor in children and adolescents, characterized by complex genetic and epigenetic alterations. Traditional treatments face significant challenges due to high rates of drug resistance and lack of targeted therapies. Recent advances in microRNA (miRNA) research have opened new avenues for understanding and treating osteosarcoma. This review explores the many critical functions of miRNAs in osteosarcoma, particularly their potential for clinical use. The review highlights two key areas where miRNAs could be beneficial. Firstly, miRNAs can act as biomarkers for diagnosing osteosarcoma and predicting patient prognosis. Secondly, specific miRNAs can regulate cellular processes like proliferation, cell death, migration, and even resistance to chemotherapy drugs in osteosarcoma. This ability to target multiple pathways within cancer cells makes miRNA-based therapies highly promising. Additionally, though the interaction between miRNAs and circular RNAs (circRNAs) falls outside the scope of the paper, it has also been discussed briefly. While miRNA-based therapies offer exciting possibilities for targeting multiple pathways in osteosarcoma, challenges remain. Efficient delivery, potential off-target effects, tumor complexity, and rigorous testing are hurdles to overcome before these therapies can reach patients. Despite these challenges, continued research and collaboration among scientists, clinicians, and regulatory bodies hold the promise of overcoming them. This collaborative effort can pave the way for the development of safe and effective miRNA-based treatments for osteosarcoma.

Targeted next-generation sequencing - a promising approach in the diagnosis of Mycobacterium tuberculosis and drug resistance.

Targeted next-generation sequencing (tNGS) offers a high-throughput, culture-independent approach that delivers a comprehensive resistance profile in a significantly shorter turn-around time, making it promising in enhancing tuberculosis (TB) diagnosis and informing treatment decisions. This study aims to evaluate the performance of tNGS in the TB diagnosis and drug resistance detection of Mycobacterium tuberculosis (MTB) using MTB clinical isolates and bronchoalveolar lavage fluid (BALF) samples. A total of 143 MTB clinical isolates were assessed, tNGS, phenotypic antimicrobial susceptibility testing (AST), and AST based on whole genome sequencing (WGS) exhibited high concordance rates, averaging 95.10% and 97.05%. Among 158 BALF samples, culture, Xpert MTB/RIF, and tNGS reported 29, 70 and 111 positives, respectively. In the confirmed cases with etiological evidence (smears, cultures, or molecular test), the positive rate of tNGS (73/83, 87.95%) was higher than that of Xpert MTB (67/83, 80.72%). Additionally, 45% (27/60) of clinically diagnosed cases (with imaging or immunological evidence) were positive for tNGS. Further validation on the discrepant results between tNGS and Xpert MTB/RIF with droplet digital PCR (ddPCR) yielded 35 positives, tNGS detected all, and Xpert MTB/RIF only identified 6 positives. In conclusion, tNGS demonstrates robust and rapid performance in the identification of MTB and its associated drug resistance, and can be directly applied to clinical samples, positioning it as a promising approach for laboratory testing of tuberculosis.

Management of Therapeutic-intensity Unfractionated Heparin: A Narrative Review on Critical Points.

Nowadays, unfractionated heparin (UFH) use is limited to selected patient groups at high risk of both bleeding and thrombosis (patients in cardiac surgery, in intensive care unit, and patients with severe renal impairment), rendering its management extremely challenging, with many unresolved questions despite decades of use. In this narrative review, we revisit the fundamental concepts of therapeutic anticoagulation with UFH and address five key points, summarizing controversies underlying the use of UFH and discussing the few recent advances in the field: (1) laboratory tests for UFH monitoring have significant limitations; (2) therapeutic ranges are not well grounded; (3) the actual influence of antithrombin levels on UFH's anticoagulant activity is not well established; (4) the concept of UFH resistance lacks supporting data; (5) scarce data are available on UFH use beyond acute venous thromboembolism. We therefore identified key issues to be appropriately addressed in future clinical research: (1) while anti-Xa assays are often considered as the preferred option, we call for a vigorous action to improve understanding of the differences between types of anti-Xa assays and to solve the issue of the usefulness of added dextran; (2) therapeutic ranges for UFH, which were defined decades ago using reagents no longer available, have not been properly validated and need to be confirmed or reestablished; (3) UFH dose adjustment nomograms require full validation.

Gene expression alterations in hypoxic A549 lung cancer cell line.

Human non-small cell lung cancer (NSCLC)is a very common disease with limited treatment options. Hypoxia is a characteristic feature of solid tumors associated with the resistance of cancer cells to radiotherapy and chemotherapy. Therefore, the expression changes in cancer-resistance genes may be biomarkers of hypoxia with value in targeted therapy. The aim of the present study was to examine the effect of hypoxia on gene expression and the changes that occur in relation to drug resistance in a human NSCLC cell line (A549). A549 cells were exposed to 72-h hypoxic episodes (<1% oxygen) for a total of 10 episodes (acute). The alterations in gene expression were examined using PCR array technology after 10 episodes of acute hypoxia and compared with normoxic cells. The chemoresistance of hypoxic cells toward doxorubicin was measured using a MTT cell proliferation assay. A549 cells were affected by acute hypoxia leading to induced doxorubicin chemoresistance. Evident changes in the gene expression level were identified following episodes of acute hypoxia. The most important changes occurred in the estrogen receptor 1 (ESR1) and Finkel-Biskis-Jinkins osteosarcoma (FOS) pathways and in different nucleic transcription factors such as aryl hydrocarbon receptor and cyclin-dependent kinase inhibitor. The present study showed that exposing cells to prolonged periods of hypoxia results in different gene expression changes. There was induction of chemo-resistance due to acute hypoxia. ESR1 and c-FOS are proposed as a potential hypoxia genes in lung cancer.

Steroidal saponins: Natural compounds with the potential to reverse tumor drug resistance (Review).

Steroidal saponins are a type of natural product that have been widely used in Chinese herbal medicine, with a variety of pharmacological activities, such as antitumor, anti-inflammatory and anti-bacterial effects. Cancer has become a growing global health problem, and drug therapy is currently the most important clinical antitumor treatment. However, drug resistance is a major obstacle to the effectiveness of chemotherapy, resulting in >90% of deaths of patients with cancer receiving conventional chemotherapy. It has been found that steroidal saponins may exert an effect on the reversal of drug resistance in tumor cells by regulating apoptosis, autophagy, epithelial-mesenchymal transition and drug efflux through multiple related signaling pathways. The present study reviews the role and mechanism of steroidal saponins in the treatment of tumor drug resistance, aiming to provide a scientific basis and research ideas for the future development and clinical application of natural steroidal saponins.