Combating anoikis resistance: bioactive compounds transforming prostate cancer therapy.

The study aims to discuss the challenges associated with treating prostate cancer (PCa), which is known for its complexity and drug resistance. It attempts to find differentially expressed genes (DEGs), such as those linked to anoikis resistance and circulating tumor cells, in PCa samples. This study involves analyzing the functional roles of these DEGs using gene enrichment analysis, and then screening of 102 bioactive compounds to identify a combination that can control the expression of the identified DEGs. In this study, 53 DEGs were identified from PCa samples including anoikis-resistant PCa cells and circulating tumor cells in PCa. Gene enrichment analysis with regards to functional enrichment of DEGs was performed. An inclusive screening process was carried out among 102 bioactive compounds to identify a combination capable of affecting and regulating the expression of selected DEGs. Eventually, gastrodin, nitidine chloride, chenodeoxycholic acid, and bilobalide were selected, as their combination demonstrated ability to modulate expression of 50 out of the 53 genes targeted. The subsequent analysis focused on investigating the biological pathways and processes influenced by this combination. The findings revealed a multifaceted and multidimensional approach to tumor regression. The combination of bioactive compounds exhibited effects on various genes including those related to production of inflammatory cytokines, cell proliferation, autophagy, apoptosis, angiogenesis, and metastasis. The current study has made a valuable contribution to the development of a combination of bioactive natural compounds that can significantly impede the development of treatment resistance in prostate tumor while countering the tumors' evasion of the immune system. The implications of this study are highly significant as it suggests the creation of an enhanced immunotherapeutic, natural therapeutic concoction with combinatorial potential.

7-amino carboxycoumarin 2 inhibits lactate induced epithelial-to-mesenchymal transition via MPC1 in oral and breast cancer cells.

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.

Canonical WNT/ß-catenin signaling upregulates aerobic glycolysis in diverse cancer types.

Despite many efforts, a comprehensive understanding and clarification of the intricate connections within cancer cell metabolism remain elusive. This might pertain to intracellular dynamics and the complex interplay between cancer cells, and cells with the tumor stroma. Almost a century ago, Otto Warburg found that cancer cells exhibit a glycolytic phenotype, which continues to be a subject of thorough investigation. Past and ongoing investigations have demonstrated intricate mechanisms by which tumors modulate their functionality by utilizing extracellular glucose as a substrate, thereby sustaining the essential proliferation of cancer cells. This concept of "aerobic glycolysis," where cancer cells (even in the presence of enough oxygen) metabolize glucose to produce lactate plays a critical role in cancer progression and is regulated by various signaling pathways. Recent research has revealed that the canonical wingless-related integrated site (WNT) pathway promotes aerobic glycolysis, directly and indirectly, thereby influencing cancer development and progression. The present review seeks to gather knowledge about how the WNT/ß-catenin pathway influences aerobic glycolysis, referring to relevant studies in different types of cancer. Furthermore, we propose the concept of impeding the glycolytic phenotype of tumors by employing specific inhibitors that target WNT/ß-catenin signaling.

Ineffective esophageal motility: Characterization and outcomes across pediatric neurogastroenterology and motility centers in the United States.

OBJECTIVES: Ineffective esophageal motility (IEM) on high-resolution manometry (HRM) is not consistently associated with specific clinical syndromes or outcomes. We evaluated the prevalence, clinical features, management, and outcomes of pediatric IEM patients across the United States. METHODS: Clinical and manometric characteristics of children undergoing esophageal HRM during 2021-2022 were collected from 12 pediatric motility centers. Clinical presentation, test results, management strategies, and outcomes were compared between children with IEM and normal HRM. RESULTS: Of 236 children (median age 15 years, 63.6% female, 79.2% Caucasian), 62 (23.6%) patients had IEM, and 174 (73.7%) patients had normal HRM, with similar demographics, medical history, clinical presentation, and median symptom duration. Reflux monitoring was performed more often for IEM patients (25.8% vs. 8.6%, p = 0.002), but other adjunctive testing was similar. Among 101 patients with follow-up, symptomatic cohorts declined in both groups in relation to the initial presentation (p > 0.107 for each comparison) with management targeting symptoms, particularly acid suppression. Though prokinetics were used more often and behavioral therapy less often in IEM (p ≤ 0.015 for each comparison), symptom outcomes were similar between IEM and normal HRM. Despite a higher proportion with residual dysphagia on follow-up in IEM (64.0% vs. 39.1%, p = 0.043), an alternate mechanism for dysphagia was identified more often in IEM (68.8%) compared to normal HRM (27.8%, p = 0.017). CONCLUSIONS: IEM is a descriptive manometric pattern rather than a clinical diagnosis requiring specific intervention in children. Management based on clinical presentation provides consistent symptom outcomes.

Biogenic synthesis of dopamine/carboxymethyl cellulose/TiO2 nanoparticles using Psidium guajava leaf extract with enhanced antimicrobial and anticancer activities.

The green synthesis of metal oxide nanoparticles (NPs) has garnered considerable attention from researchers due to its utilization of eco-friendly solvents during synthesis and cost-effective approaches. This study focuses on the synthesis of titanium oxide (TiO2) and dopamine (DA) carboxymethyl cellulose (CMC)-doped TiO2 (DA/CMC/TiO2) NP using Psidium guajava leaf extract, while also investigating the structural, optical, and morphological and biocidal potential of the prepared NPs. Significantly larger zones of inhibition were observed for DA/CMC/TiO2 NPs compared to TiO2 against various pathogens. Moreover, the MTT assay was carried out to evaluate the anticancer activity of the prepared samples against MG-63 cells, and the results revealed that DA/CMC/TiO2 NPs exhibited significantly higher level of anticancer activity compared to TiO2. The experimental results demonstrated that DA/CMC/TiO2 NPs exhibited enhanced anticancer activity in a dose-dependent manner when compared to TiO2 NPs.

Application of Pathfinding Algorithms in Partial Discharge Localization in Power Transformers.

The introduction of artificial intelligence (AI) to ultra-high-frequency (UHF) partial discharge (PD) monitoring systems in power transformers for the localization of PD sources can help create a robust and reliable system with high usability and precision. However, training the AI with experimental data or data from electromagnetic simulation is costly and time-consuming. Furthermore, electromagnetic simulations often calculate more data than needed, whereas, for localization, the signal time-of-flight information is the most important. A tailored pathfinding algorithm can bypass the time-consuming and computationally expensive process of simulating or collecting data from experiments and be used to create the necessary training data for an AI-based monitoring system of partial discharges in power transformers. In this contribution, Dijkstra's algorithm is used with additional line-of-sight propagation algorithms to determine the paths of the electromagnetic waves generated by PD sources in a three-dimensional (3D) computer-aided design (CAD) model of a 300 MVA power transformer. The time-of-flight information is compared with results from experiments and electromagnetic simulations, and it is found that the algorithm maintains accuracy similar to that of the electromagnetic simulation software, with some under/overestimations in specific scenarios, while being much faster at calculations.

Assessment and estimation of coal dust impact on vegetation using VIs difference model and PRISMA hyperspectral data in mining sites.

This work focuses on dust detection, and estimation of vegetation in coal mining sites using the vegetation indices (VIs) differences model and PRISMA hyperspectral imagery. The results were validated by ground survey spectral and foliar dust data. The findings indicate that the highest Separability (S), Coefficient of discrimination (R2), and lowest Probability (P) values were found for the narrow-banded Narrow-banded Normalized Difference Vegetation Index (NDVI), Transformed Soil Adjusted Vegetation Index (TSAVI), and Tasselled Cap Transformation Greenness (TC-greenness) indices. These indices have been utilized for the Vegetation Combination (VC) index analysis. Compared to other VC indices, this VC index revealed the highest difference (29.77%), which led us to employ this index for the detection of healthy and dust-affected areas. The foliar dust model was developed for the estimation and mapping of dust impact on vegetation using the VIs differences models (VIs diff models), laboratory dust amounts, and leaf spectral regression analysis. Based on the highest R2 (0.90), the narrow-banded TC-greenness differenced VI was chosen as the best VI, and the coefficient (L) value (-7.75gm/m2) was used for estimating the amount of foliar dust in coal mining sites. Compared to other indices-based difference dust models, the narrow-banded TC-greenness difference image had the highest R2 (0.71) and lowest RMSE (4.95 gm/m2). According to the findings, the areas with the highest dust include those with mining haul roads, transportation, rail lines, dump areas, tailing ponds, backfilling, and coal stockyard sides. This study also showed a significant inverse relationship (R2 = 0.84) among vegetation dust classes, leaf canopy spectrum, and distance from mines. This study provides a new way for estimating dust on vegetation based on advanced hyperspectral remote sensing (PRISMA) and field spectral analysis techniques that may be helpful for vegetation dust monitoring and environmental management in mining sites.

Modern pollen dispersal in relation to present vegetation distribution and land use in the Baspa valley, Kinnaur, western Himalayas.

Interpretation of a fossil pollen data for the vegetation and climate reconstruction of any region needs a modern pollen-vegetation analogue for its calibration. We analyzed the surface sediments and moss polsters for the pollen and microcharcoal records to understand the modern pollen-vegetation relationship and human activities in the Baspa Valley, Kinnaur, Himachal Pradesh. Presently, valley is occupied by the arboreal and non-arboreal vegetation of temperate to subalpine habitats and land use activities. The recovered pollen assemblages showed variability in the dispersal behavior of pollen of taxa growing along the valley transect and also captured the signals of human activities over land use. The overall dominance of arboreal pollen in the recovered pollen assemblage corresponds with the dominant growth of conifers and broadleaf tree taxa and represents the valley vegetation at a regional scale. However, the profuse pollen production of a few arboreal taxa and long distance pollen transport from one vegetation zone to other by the strong upthermic valley winds could bias the pollen representation of in-situ vegetation. The high pollen frequency of non-arboreal taxa in the open meadows represents the near vicinity to their plant source. Human activities like fire burning and cultivation by the local population are evident by the recovery of microcharcoal particles and pollen of plants belonging to Cerealia Poaceae, Asteraceae, Amaranthaceae, Polygonaceae, Rosaceae, Juglandaceae, etc. The dataset taken as modern pollen-vegetation analogue is useful to assess past changes in the vegetation and land cover in relation to climate and human factors for future sustenance.

Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis.

Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the elevated glycolytic pathway has been linked to their aggressive phenotype. In the present study, we evaluated the prognostic and therapeutic relevance of PFKFB3 (6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase) in TNBCs. Prognostic significance of PFKFB3 expression was evaluated in overall breast cancers as well as in TNBCs. PFKFB3 inhibitor (3PO potent analogue i.e., PFK15) cytotoxicity in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was analyzed using an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cancer cell physiological characteristics like clonogenicity and migration were also investigated after PFK15 treatment. As fructose-2,6-bisphosphate (F-2,6-BP), has been associated with increased PFK-1 activity, the effect of PFKFB3 inhibition by PFK15 was investigated on two major isoforms of phosphofructokinase-1 (PFK-1) in breast cancer, that is, phosphofructokinase-platelet type (PFKP) and phosphofructokinase-liver type (PFKL) (relevant to breast cancer). For PFKL inhibition, the siRNA approach was used. PFKFB3 expression was significantly correlated with inferior overall survival in breast cancer patients including TNBCs. PFK15 treatment in TNBC cells (i.e., MDA-MB-231 and MDA-MB-468) resulted in a decreased PFKP expression, thereby leading to reduced colony formation ability, migration rate, and extracellular lactate levels. However, to our surprise PFK15 treatment in both TNBC cells also resulted in elevated PFKL levels. Our results demonstrated that the combinatorial inhibition of PFK15 with siPFKL was more effective in TNBC cells, as it led to a decrease in colony formation ability, migration rate, extracellular lactate levels, and PFK-1 activity when compared with individual treatments. Using bona fide PFKFB3 inhibitor, that is, AZ67, we further show that AZ67 treatment to TNBC cells has no effect either on the expression of PFKP and PFKL, or on the lactate production. In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients.

Ten-year distant-recurrence risk prediction in breast cancer by CanAssist Breast (CAB) in Dutch sub-cohort of the randomized TEAM trial.

BACKGROUND: Hormone receptor (HR)-positive, HER2/neu-negative breast cancers have a sustained risk of recurrence up to 20 years from diagnosis. TEAM (Tamoxifen, Exemestane Adjuvant Multinational) is a large, multi-country, phase III trial that randomized 9776 women for the use of hormonal therapy. Of these 2754 were Dutch patients. The current study aims for the first time to correlate the ten-year clinical outcomes with predictions by CanAssist Breast (CAB)-a prognostic test developed in South East Asia, on a Dutch sub-cohort that participated in the TEAM. The total Dutch TEAM cohort and the current Dutch sub-cohort were almost similar with respect to patient age and tumor anatomical features. METHODS: Of the 2754 patients from the Netherlands, which are part of the original TEAM trial, 592 patients' samples were available with Leiden University Medical Center (LUMC). The risk stratification of CAB was correlated with outcomes of patients using logistic regression approaches entailing Kaplan-Meier survival curves, univariate and multivariate cox-regression hazards model. We used hazard ratios (HRs), the cumulative incidence of distant metastasis/death due to breast cancer (DM), and distant recurrence-free interval (DRFi) for assessment. RESULTS: Out of 433 patients finally included, the majority, 68.4% had lymph node-positive disease, while only a minority received chemotherapy (20.8%) in addition to endocrine therapy. CAB stratified 67.5% of the total cohort as low-risk [DM = 11.5% (95% CI, 7.6-15.2)] and 32.5% as high-risk [DM = 30.2% (95% CI, 21.9-37.6)] with an HR of 2.90 (95% CI, 1.75-4.80; P < 0.001) at ten years. CAB risk score was an independent prognostic factor in the consideration of clinical parameters in multivariate analysis. At ten years, CAB high-risk had the worst DRFi of 69.8%, CAB low-risk in the exemestane monotherapy arm had the best DRFi of 92.7% [vs CAB high-risk, HR, 0.21 (95% CI, 0.11-0.43), P < 0.001], and CAB low-risk in the sequential arm had a DRFi of 84.2% [vs CAB high-risk, HR, 0.48 (95% CI, 0.28-0.82), P = 0.009]. CONCLUSIONS: Cost-effective CAB is a statistically robust prognostic and predictive tool for ten-year DM for postmenopausal women with HR+/HER2-, early breast cancer. CAB low-risk patients who received exemestane monotherapy had an excellent ten-year DRFi.

Esophageal Hypervigilance and Visceral Anxiety Contribute to Symptom Severity of Laryngopharyngeal Reflux.

INTRODUCTION: Laryngopharyngeal reflux (LPR) is a clinical conundrum without a diagnostic gold standard. The Esophageal Hypervigilance and Anxiety Scale (EHAS) is a questionnaire designed for cognitive-affective evaluation of visceral sensitivity. We hypothesized that esophageal hypervigilance and symptom-specific anxiety have an etiopathological role in generation of LPR symptoms, especially when gastroesophageal reflux disease (GERD) cannot explain these symptoms. METHODS: Consecutive patients with LPR and/or GERD symptoms lasting >3 months were prospectively enrolled and characterized using the Reflux Symptom Index, GERD questionnaire, and EHAS. Eligible patients with negative endoscopy underwent 24-hour impedance-pH monitoring off acid suppression for phenotyping GERD and assessment of reflux burden, using conventional metrics (acid exposure time and number of reflux episodes) and novel metrics (mean nocturnal baseline impedance and postreflux swallow-induced peristaltic wave index). RESULTS: Of 269 enrolled patients (mean age 47.1 years, 21-65 years, 60.6% female), 90 patients were with concomitant GERD and LPR symptoms, 32 patients were with dominant LPR symptoms, 102 patients were with dominant GERD symptoms, and 45 were controls. Patients with concomitant GERD and LPR symptoms had higher EHAS than those with dominant GERD symptoms and controls ( P ≤ 0.001); patients with dominant LPR symptoms had higher EHAS than controls ( P = 0.007). On Pearson correlation, EHAS positively correlated with the Reflux Symptom Index. DISCUSSION: Esophageal hypervigilance and symptom-specific anxiety may be more important than reflux burden in LPR symptom perception.

Antibiotics and nano-antibiotics in treatment of lung infection: In management of COVID-19.

The world has witnessed the cruelty of COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The association of COVID-19 with other secondary and bacterial co-infections has tremendously contributed to lung infections. An increased probability of having a secondary lung infection was observed among the post-COVID patients. The treatment of antibiotics has ameliorated the mortality rate. However, the stewardship of antibiotic treatment was linked to increased organ failure. Therefore, the paper discusses the interactions between the virus and host through the ACE2 receptors that contribute to COVID-19 development. Furthermore, the paper provides an invaluable compendium history of SARS-CoV-2 genomic composition. It revolves around most classes of antibiotics used to treat COVID-19 disease and post-COVID lung infections with the complete mechanism. This binds with the exertion of the antibiotics for bacterial infection associated with COVID-19 patients and how beneficial and effective responses have been recorded for the treatment. The application of nanotechnology and possible approaches of nanomedicines is also discussed to its potential usage.

Passage number of cancer cell lines: Importance, intricacies, and way-forward.

Cancer cell lines play a crucial role as invaluable models in cancer research, facilitating the examination of cancer progression as well as the advancement of diagnostics and treatments. While they may not perfectly replicate the original tumor, they generally exhibit similar characteristics. Low-passage cancer cell lines are generally preferred due to their closer resemblance to the original tumor, as long-term culturing can alter the genetic and molecular profiles of a cell line thereby highlighting the importance of monitoring the passage number (PN). Variations in proliferation, migration, gene expression, and drug sensitivity can be linked to PN differences. PN can also influence DNA methylation levels, metabolic profiles, and the expression of genes/or proteins in cancer cell lines. When conducting research on cancer cell lines, it is crucial for researchers to carefully select the appropriate PN to maintain consistency and reliability of results. Moreover, to ensure dependability and replicability, scientists ought to actively track the growth, migration, and gene/or protein profiles of cancer cell lines at specific PNs. This approach enables the identification of the most suitable range of PNs for experiments, guaranteeing consistent and precise results. Additionally, such efforts serve to minimize disparities and uphold the integrity of research. In this review, we have laid out recommendations for laboratories to overcome these PN discrepancies when working with cancer cell lines.

Discovery of non-nucleoside oxindole derivatives as potent inhibitors against dengue RNA-dependent RNA polymerase.

A series of thiazole linked Oxindole-5-Sulfonamide (OSA) derivatives were designed as inhibitors of RNA-dependent RNA polymerase (RdRp) activity of Dengue virus. These were synthesized and then evaluated for their efficacy in ex-vivo virus replication assay using human cell lines. Among 20 primary compounds in the series, OSA-15 was identified as a hit. A series of analogues were synthesized by replacing the difluoro benzyl group of OSA-15 with different substituted benzyl groups. The efficacy of OSA-15derivatives was less than that of the parent compound, except OSA-15-17, which has shown improved efficacy than OSA-15. The further optimization was carried out by adding dimethyl (DM) groups to both the sulfonamide and oxindole NH's to produce OSA-15-DM and OSA-15-17-DM. These two compounds were showing no detectable cytotoxicity and the latter was more efficacious. Further, both these compounds were tested for inhibition in all the serotypes of the Dengue virus using an ex-vivo assay. The EC50 of OSA-15-17-DM was observed in a low micromolar range between 2.5 and 5.0 µg/ml. Computation docking and molecular dynamics simulation studies confirmed the binding of identified hits to DENV RdRp. OSA15-17-DM blocks the RNA entrance and elongation site for their biological activity with high binding affinity. Overall, the identified oxindole derivatives are novel compounds that can inhibit Dengue replication, working as non-nucleoside inhibitors (NNI) to explore as anti-viral RdRp activity.

Outcomes of very preterm infants with hyperglycaemia treated with insulin: A systematic review and meta-analysis.

AIM: To study the outcomes of very preterm infants with hyperglycaemia treated with Insulin. METHODS: This is a systematic review of randomised controlled trials (RCTs) and observational studies. PubMed, Medline, EMBASE, Cochrane Library, EMCARE and MedNar databases were searched in May 2022. Data were pooled separately for adjusted and unadjusted odds ratios (ORs) using random-effects model. MAIN OUTCOME MEASURES: Mortality and morbidities (e.g. Necrotising enterocolitis [NEC], retinopathy of prematurity [ROP]) in very preterm (<32 weeks) or very low birth weight infants (<1500 g) after treatment of hyperglycaemia with insulin. RESULTS: Sixteen studies with data from 5482 infants were included. Meta-analysis of unadjusted ORs from cohort studies showed that insulin treatment was significantly associated with increased mortality [OR 2.98 CI (1.03 to 8.58)], severe ROP [OR 2.23 CI (1.34 to 3.72)] and NEC [OR 2.19 CI (1.11 to 4)]. However, pooling of adjusted ORs did not show significant associations for any outcomes. The only included RCT found better weight gain in the insulin group, but no effect on mortality or morbidities. Certainty of evidence was 'Low' or 'Very low'. CONCLUSION: Very low certainty evidence suggests that Insulin therapy may not improve outcomes of very preterm infants with hyperglycaemia.

Quantum Sensing of Free Radicals in Primary Human Dendritic Cells.

Free radicals are crucial indicators for stress and appear in all kinds of pathogenic conditions, including cancer, cardiovascular diseases, and infection. However, they are difficult to detect due to their reactivity and low abundance. We use relaxometry for the detection of radicals with subcellular resolution. This method is based on a fluorescent defect in a diamond, which changes its optical properties on the basis of the magnetic surroundings. This technique allows nanoscale MRI with unprecedented sensitivity and spatial resolution. Recently, this technique was used inside living cells from a cell line. Cell lines differ in terms of endocytic capability and radical production from primary cells derived from patients. Here we provide the first measurements of phagocytic radical production by the NADPH oxidase (NOX2) in primary dendritic cells from healthy donors. The radical production of these cells differs greatly between donors. We investigated the cell response to stimulation or inhibition.

A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation.

The methyltransferase activity of the trithorax group (TrxG) protein MLL1 found within its COMPASS (complex associated with SET1)-like complex is allosterically regulated by a four-subunit complex composed of WDR5, RbBP5, Ash2L, and DPY30 (also referred to as WRAD). We report structural evidence showing that in WRAD, a concave surface of the Ash2L SPIa and ryanodine receptor (SPRY) domain binds to a cluster of acidic residues, referred to as the D/E box, in RbBP5. Mutational analysis shows that residues forming the Ash2L/RbBP5 interface are important for heterodimer formation, stimulation of MLL1 catalytic activity, and erythroid cell terminal differentiation. We also demonstrate that a phosphorylation switch on RbBP5 stimulates WRAD complex formation and significantly increases KMT2 (lysine [K] methyltransferase 2) enzyme methylation rates. Overall, our findings provide structural insights into the assembly of the WRAD complex and point to a novel regulatory mechanism controlling the activity of the KMT2/COMPASS family of lysine methyltransferases.

Comparative Diagnostic of Cervical Tuberculous Lymphadenitis: PCR is a Fast, Efficient, and Improved Diagnostic Approach.

Methods: The study included 100 clinically suspected cases of TBLN. Fine needle aspirate (FNA) samples were processed for cytology staining and cultured on LJ & BACTEC 12B media. The biochemical tests were performed to identify the isolates at the species level. Additionally, for PCR, DNA was extracted and used for the diagnosis and identification of mycobacterial species. Results: Patients ranged from 2 to 45 years with a mean age of 24.96 ± 9.10 years. Out of 100 patients, 73% had clinical symptoms of weight loss, followed by fever (72%), anorexia (66%), and night sweats (58%). 24% of patients were found to be smear-positive after Ziehl-Neelsen (ZN) staining and statistically highly significant with PCR. On LJ medium 34% and on BACTEC radiometric 45% of samples were smearing positive. Overall, 48% of cases were PCR-positive for TBLN. When compared with culture, the sensitivity and specificity of PCR were 93.75% and 100%, respectively, which are higher than cytology. The true positive predictive value (PPV) and negative predictive value (NPV) were 83.3% and 61.5%, respectively. Conclusion: This study suggests that PCR is a rapid, sensitive, and specific tool for correct diagnosis of TBLN cases as compared to staining and culture which lead to the early and proper management of mycobacterial diseases.

Bendamustine in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: A phase II trial.

Treatment of patients with resistant/refractory multiple myeloma (MM) is an unmet need. In this phase II study, we evaluated the role of bendamustine, pomalidomide and dexamethasone combination in this setting. Between February 2020 and December 2021, 28 patients were recruited. Patients received bendamustine 120 mg/m2 day 1, pomalidomide 3 mg days 1-21, and dexamethasone 40 mg days 1, 8, 11, 22, regimen given for a maximum of six cycles. The median (range) age of the patients was 54 (30-76) years and 15 (53.6%) were males. Patients had received a median (range) of three (two-six) prior lines and 85.7% were refractory to both lenalidomide and bortezomib. The primary end-point was the overall response rate (ORR) defined as ≥partial response after at least three cycles. Secondary objectives were toxicity, progression-free survival (PFS), time to progression and overall survival (OS). An intent-to-treat analysis was done. An ORR of 57.6% was achieved. Patients with extramedullary myeloma had a better response rate. At a median follow-up of 8.6 months, the median PFS and OS were 6.2 and 9.7 months respectively. Toxicity was manageable; mainly haematological (neutropenia, 46.4%; anaemia, 42.8%; and thrombocytopenia, 7.1%). Bendamustine, pomalidomide and dexamethasone could be a novel combination for the heavily pretreated, lenalidomide-refractory myeloma population.

Quercetin Impairs HuR-Driven Progression and Migration of Triple Negative Breast Cancer (TNBC) Cells.

In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online meta-analysis tool, we found that HuR protein overexpression positively correlates with reduced overall survival of TNBC patients (p = 0.028). Furthermore, we demonstrated that the TNBC breast cancer cell lines i.e., MDA-MB-231 and MDA-MB-468 are good model systems to study HuR protein, as they both exhibit a significant amount of cytoplasmic HuR (active form). Quercetin treatment significantly inhibited the cytoplasmic HuR in both TNBC cell lines. By using specific HuR siRNA, we established that quercetin-mediated inhibition of adhesion and migration of TNBC cells is dependent on HuR. Upon analyzing adhesion proteins i.e., ß-catenin and CD44, we found that quercetin mediated effect on TNBC adhesion and migration was through the HuR-ß-catenin axis and CD44, independently. Overall, the present results demonstrate that elevated HuR levels are associated with TNBC progression and relapse, and the ability of quercetin to inhibit cytoplasmic HuR protein provides a rationale for using it as an anticancer agent for the treatment of aggressive TNBCs.Supplemental data for this article is available online at at 10.1080/01635581.2021.1952628.