A role for microsomal glutathione transferase 1 in melanin biosynthesis and melanoma progression.

Recent advancements in the treatment of melanoma are encouraging, but there remains a need to identify additional therapeutic targets. We identify a role for microsomal glutathione transferase 1 (MGST1) in biosynthetic pathways for melanin and as a determinant of tumor progression. Knockdown (KD) of MGST1 depleted midline-localized, pigmented melanocytes in zebrafish embryos, while in both mouse and human melanoma cells, loss of MGST1 resulted in a catalytically dependent, quantitative, and linear depigmentation, associated with diminished conversion of L-dopa to dopachrome (eumelanin precursor). Melanin, especially eumelanin, has antioxidant properties, and MGST1 KD melanoma cells are under higher oxidative stress, with increased reactive oxygen species, decreased antioxidant capacities, reduced energy metabolism and ATP production, and lower proliferation rates in 3D culture. In mice, when compared to nontarget control, Mgst1 KD B16 cells had less melanin, more active CD8+ T cell infiltration, slower growing tumors, and enhanced animal survival. Thus, MGST1 is an integral enzyme in melanin synthesis and its inhibition adversely influences tumor growth.

Inoculation of heavy metal resistant bacteria alleviated heavy metal-induced oxidative stress biomarkers in spinach (Spinacia oleracea L.).

Most vegetable crops are severely affected by the uptake of heavy metals from the soil. Heavy metals in vegetable bodies generate reactive oxygen species (ROS) that unbalance the antioxidant defense system. This study was initiated to determine the physiological and biochemical characteristics of spinach plants grown on soil contaminated with heavy metals and responding to Bacillus cereus and Bacillus aerius were isolated from soil contaminated with heavy metals. Heavy metal contamination led to a significant reduction in seed germination, seedling biomass, protein, and total nitrogen content of spinach plants grown in contaminated soils compared to control soils. In contrast, a significant increase in the content of metallothioneins and antioxidant enzymes was observed. Plants inoculated with B. cereus and B. aerius significantly reduced the oxidative stress induced by heavy metals by improving seed germination (%), seedling growth, nitrogen, and protein content. The content of metallothioneins and the activities of antioxidant enzymes were reduced in spinach plants grown from seeds inoculated with bacterial strains. In addition, plants inoculated with, B. cereus and B. aerius showed greater stomata opening than plants grown on soil contaminated with heavy metals, whose stomata were almost closed. These results suggested that both bacterial strains enhanced plant growth by reducing oxidative stress caused by metals.

Diversity and ecological function of urease-producing bacteria in the cultivation environment of Gracilariopsis lemaneiformis.

Urease-producing bacteria (UPB) provide inorganic nitrogen for primary producers by hydrolyzing urea, and play an important role in marine nitrogen cycle. However, there is still an incomplete understanding of UPB and their ecological functions in the cultivation environment of the red macroalgae Gracilariopsis lemaneiformis. This study comprehensively analyzed the diversity of culturable UPB and explored their effects on urea uptake by G. lemaneiformis. A total of 34 isolates belonging to four main bacterial phyla i.e. (Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria) were identified through 16S rRNA sequencing and were screened for UPB by urea agar chromogenic medium assay and ureC gene cloning. Our data revealed that only 8 strains contained urease. All of these UPB exhibited different urease activities, which were determined by the Berthelot reaction colorimetry assay. Additionally, the UPB strain (G13) isolated from G. lemaneiformis with higher urease activity was selected for co-culture with G. lemaneiformis to explore its role in promoting or inhibiting nitrogen uptake by macroalgae. The results showed a significant increase in urea consumption in the culture medium and the total cellular nitrogen in G. lemaneiformis in the UPB-co culture group compared to the sterile group. This suggests that the selected UPB strain positively influences nitrogen uptake by G. lemaneiformis. Similarly, isotopic assays revealed that the δ15N content of G. lemaneiformis was significantly higher in the UPB-co culture than in the control group, where δ15N-urea was the only nitrogen source in the culture medium. This indicates that the UPB helped G. lemaneiformis to absorb more nitrogen from urea. Moreover, the highest content of δ15N was found in G. lemaneiformis with epiphytic bacteria compared to sterilized (i.e. control), showing that epiphytic bacteria, along with UPB, have a compound effect in helping G. lemaneiformis absorb more nitrogen from urea. Taken together, these results provide unique insight into the ecological role of UPB and suggest that urease from macroalgae environment-associated bacteria might be an important player in marine nitrogen cycling.

Evaluation of soil texture classification from orthodox interpolation and machine learning techniques.

The current investigation examines the effectiveness of various approaches in predicting the soil texture class (clay, silt, and sand contents) of the Rawalpindi district, Punjab province, Pakistan. The employed techniques included artificial neural networks (ANNs), kriging, co-kriging, and inverse distance weighting (IDW). A total of 44 soil specimens from depths of 10-15 cm were gathered, and then the hydrometer method was adopted to measure their texture. The map of soil grain sets was formulated in the ArcGIS environment, utilizing distinct interpolation approaches. The MATLAB software was used to evaluate soil texture. The gradient fraction, latitude and longitude, elevation, and soil texture fragments of points were proposed to an ANN. Several statistical values, such as correlation coefficient (R), geometric mean error ratios (GMER), and root mean square error (RMSE), were utilized to evaluate the precision of the intended techniques. In assessing grain size and spatial dissemination of clay, silt, and sand, the effectiveness and precision of ANN were superior compared to kriging, co-kriging, and inverse distance weighting. Still, less than a 50% correlation was observed using the ANN. In this examination, the IDW had inferior precision compared to the other approaches. The results demonstrated that the practices produced acceptable results and can be used for future research. Soil texture is among the most central variables that can manipulate agriculture plans. The prepared maps exhibiting the soil texture groups are imperative for crop yield and pastoral scheduling.

Midurethral Sling Mesh Exposure Confers a High Risk of Persistent Stress Urinary Incontinence.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the relationship between mesh exposure and persistent stress urinary incontinence (SUI) post-midurethral sling (MUS) surgery. METHODS: Extensive data collection including patient demographics, obstetric history, existing medical conditions, previous surgeries, and surgical outcomes, encompassing both perioperative and postoperative complications. RESULTS: Out of 456 patients who underwent the MUS procedure within the specified period, the persistence of SUI was noted in 6.4% of cases. Mesh exposure was observed in 8.8% of these cases. Notably, 25% of patients with mesh exposure suffered from persistent SUI, in stark contrast to 4.6% of those without mesh exposure (p < 0.0001). Further, multivariate analysis indicated that patients with mesh exposure had an approximately 6.5-fold increased likelihood (95% CI: 2.71-15.44) of experiencing persistent SUI compared with those without mesh exposure. CONCLUSIONS: Mesh exposure is a significant independent risk factor for persistent SUI post-MUS surgery. Patients with mesh exposure are about 6.5 times more prone to persistent SUI than those without. Although mesh exposure is typically managed with expectant measures, vaginal estrogen or mesh excision, current evidence does not support surgical revision of MUS affected by mesh exposure or additional incontinence procedures during mesh excision.

Disparities with global standards about growth references of mid-upper arm circumference-for-age for Pakistani children aged 6-60 months.

AIM: Growth reference values about mid-upper arm circumference (MUAC) are vital for assessing children's nutritional status. However, Pakistan lacks these reference values and growth charts. This study aims to develop these for children aged 6-60 months and compare them with global standards. METHODS: The data were acquired from the 2018 National Nutrition Survey of Pakistan, which was conducted by the United Nations Children's Fund (UNICEF) during 2018-2019. The final study cohort comprised 57 285 children, with 51% being boys. Percentile values and charts for MUAC-for-age were developed using generalised additive models for location, scale and shape with the Box-Cox power exponential distribution. RESULTS: The mean MUAC was 14.21 cm (±2.07 cm) and 14.13 cm (±2.12 cm) for the boys and girls, respectively. At 60 months of age, the P3 and P97 percentiles for girls were slightly higher than those for boys. The median percentiles of Pakistani children were smaller than the World Health Organisation 2007 standards and with international references. CONCLUSION: We observed disparities in MUAC-for-age growth references among Pakistani children compared to global standards, highlighting regional, age and gender variations. This underscores the need for developing countries like Pakistan to establish their growth references.

Midurethral Sling With Concomitant Sacrocolpopexy: Does the Sequence Matter? A Retrospective Cohort Study.

The objective is to determine if the timing of midurethral sling (MUS) placement has an impact on the recurrence rate of stress urinary incontinence. We conducted a retrospective cohort study of patients who underwent robot sacrocolpopexy (RSC) with MUS placement at a large community hospital. Our data demonstrated that there was no significant difference in stress urinary incontinence recurrence when the MUS was placed before or after the RSC (15% vs. 11%, P = 0.41, respectively). We concluded that physician preference may dictate surgical approach to sequence of retropubic MUS placement at the time of RSC.

Evaluation of heavy metal accumulation and tolerance in oxalic acid-treated Phragmites australis wetlands for textile effluent remediation.

Water contamination with metals poses significant environmental challenges. The occurrence of heavy metals (HMs) prompts modifications in plant structures, emphasizing the necessity of employing focused safeguarding measures. Cadmium (Cd), lead (Pb), and chromium (Cr) emerge as particularly menacing toxins due to their high accumulation potential. Increasing the availability of organic acids is crucial for optimizing toxic metal removal via phytoremediation. This constructed wetland system (CWs) was used to determine how oxalic acid (OA) treatments of textile wastewater (WW) effluents affected morpho-physiological characteristics, antioxidant enzyme activity, oxidative stress, and HM concentrations in Phragmites australis. Multiple treatments, comprising the application of OA at a concentration of 10 mM and WW at different dilutions (25%, 50%, 75%, and 100%), were employed, with three replications of each treatment. WW stress decreased chlorophyll and carotenoid content, and concurrently enhanced HMs adsorption and antioxidant enzyme activities. Furthermore, the application of WW was found to elevate oxidative stress levels, whereas the presence of OA concurrently mitigated this oxidative stress. Similarly, WW negatively affected soil-plant analysis development (SPAD) and the total soluble proteins (SP) in both roots and shoots. Conversely, these parameters showed improvement with OA treatments. P. australis showed the potential to enhance HM accumulation under 100% WW stress. Specifically, there is an increase in root SP ranging from 9% to 39%, an increase in shoot SP from 6% to 91%, and an elevation in SPAD values from 4% to 64% compared to their respective treatments lacking OA inclusion. The OA addition resulted in decreased EL contents in the root and shoot by 10%-19% and 13%-15%, MDA by 9%-14% and 9%-20%, and H2O2 by 14%-21% and 9%-17%, in comparison to the respective treatments without OA. Interestingly, the findings further revealed that the augmentation of OA also contributed to an increased accumulation of Cr, Cd, and Pb. Specifically, at 100% WW with OA (10 mM), the concentrations of Cr, Pb, and Cd in leaves rose by 164%, 447%, and 350%, in stems by 213%, 247%, and 219%, and in roots by 155%, 238%, and 195%, respectively. The chelating agent oxalic acid effectively alleviated plant toxicity induced by toxins. Overall, our findings demonstrate the remarkable tolerance of P. australis to elevated concentrations of WW stress, positioning it as an eco-friendly candidate for industrial effluent remediation. This plant exhibits efficacy in restoring contaminants present in textile effluents, and notably, oxalic acid emerges as a promising agent for the phytoextraction of HMs.

HMs stress decreased the physiology and morphology of Phragmites australis L.OA improved the photosynthetic pigments and antioxidant enzymesHMs accumulation and bioavailability increased under OAPhragmites australis L. showed higher efficacy for textile effluent treatment under OA.

Electric Potential at the Interface of Membraneless Organelles Gauged by Graphene.

Eukaryotic cells contain membrane-bound and membrane-less organelles that are often in contact with each other. How the interface properties of membrane-less organelles regulate their interactions with membranes remains challenging to assess. Here, we employ graphene-based sensors to investigate the electrostatic properties of synapsin 1, a major synaptic phosphoprotein, either in a single phase or after undergoing phase separation to form synapsin condensates. Using these graphene-based sensors, we discover that synapsin condensates generate strong electrical responses that are otherwise absent when synapsin is present as a single phase. By introducing atomically thin dielectric barriers, we show that the electrical response originates in an electric double layer whose formation governs the interaction between synapsin condensates and graphene. Our data indicate that the interface properties of the same protein are substantially different when the protein is in a single phase versus within a biomolecular condensate, unraveling that condensates can harbor ion potential differences at their interface.

The Transcription Factor MiMYB8 Suppresses Peel Coloration in Postharvest 'Guifei' Mango in Response to High Concentration of Exogenous Ethylene by Negatively Modulating MiPAL1.

Anthocyanin accumulation is regulated by specific genes during fruit ripening. Currently, peel coloration of mango fruit in response to exogenous ethylene and the underlying molecular mechanism remain largely unknown. The role of MiMYB8 on suppressing peel coloration in postharvest 'Guifei' mango was investigated by physiology detection, RNA-seq, qRT-PCR, bioinformatics analysis, yeast one-hybrid, dual-luciferase reporter assay, and transient overexpression. Results showed that compared with the control, low concentration of exogenous ethylene (ETH, 500 mg·L-1) significantly promoted peel coloration of mango fruit (cv. Guifei). However, a higher concentration of ETH (1000 mg·L-1) suppressed color transformation, which is associated with higher chlorophyll content, lower a* value, anthocyanin content, and phenylalanine ammonia-lyase (PAL) activity of mango fruit. M. indica myeloblastosis8 MiMYB8 and MiPAL1 were differentially expressed during storage. MiMYB8 was highly similar to those found in other plant species related to anthocyanin biosynthesis and was located in the nucleus. MiMYB8 suppressed the transcription of MiPAL1 by binding directly to its promoter. Transient overexpression of MiMYB8 in tobacco leaves and mango fruit inhibited anthocyanin accumulation by decreasing PAL activity and down-regulating the gene expression. Our observations suggest that MiMYB8 may act as repressor of anthocyanin synthesis by negatively modulating the MiPAL gene during ripening of mango fruit, which provides us with a theoretical basis for the scientific use of exogenous ethylene in practice.

Revolutionizing tumor detection and classification in multimodality imaging based on deep learning approaches: methods, applications and limitations.

BACKGROUND: The emergence of deep learning (DL) techniques has revolutionized tumor detection and classification in medical imaging, with multimodal medical imaging (MMI) gaining recognition for its precision in diagnosis, treatment, and progression tracking. OBJECTIVE: This review comprehensively examines DL methods in transforming tumor detection and classification across MMI modalities, aiming to provide insights into advancements, limitations, and key challenges for further progress. METHODS: Systematic literature analysis identifies DL studies for tumor detection and classification, outlining methodologies including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and their variants. Integration of multimodality imaging enhances accuracy and robustness. RESULTS: Recent advancements in DL-based MMI evaluation methods are surveyed, focusing on tumor detection and classification tasks. Various DL approaches, including CNNs, YOLO, Siamese Networks, Fusion-Based Models, Attention-Based Models, and Generative Adversarial Networks, are discussed with emphasis on PET-MRI, PET-CT, and SPECT-CT. FUTURE DIRECTIONS: The review outlines emerging trends and future directions in DL-based tumor analysis, aiming to guide researchers and clinicians toward more effective diagnosis and prognosis. Continued innovation and collaboration are stressed in this rapidly evolving domain. CONCLUSION: Conclusions drawn from literature analysis underscore the efficacy of DL approaches in tumor detection and classification, highlighting their potential to address challenges in MMI analysis and their implications for clinical practice.

Development of a robust method for Cd(II) ions analysis using CeO2- and CeO2-Cu-BTC-based electrochemical sensors.

Simple and sensitive electrochemical sensors were fabricated from cerium oxide (CeO2) and copper-benzene tricarboxylic acid-modified cerium oxide (CeO2-Cu-BTC) materials for differential pulse voltammetric analysis of toxic cadmium (Cd) ions in aqueous solutions. The materials were prepared by hydrothermal method and structurally characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy with energy-dispersive X-ray (SEM-EDX), thermogravimetric analysis (TGA), and X-ray diffraction analysis (XRD). The CeO2-modified carbon paste electrode (CeCPE) and the CeO2-Cu-BTC-modified carbon paste electrode (CeBCPE) were electrochemically characterized by their cyclic voltammetry and electrochemical impedance study in standard K3[Fe(CN)6] single-electron redox process. Their electrochemical surface areas, electrode surface coverages, and charge transfer resistances were calculated to be 1.46 cm2, 2.338 × 10-5 mol∙cm-2, and 2790 Ω and 5.48 cm2, 2.476 × 10-5 mol∙cm-2, and 1254.65 Ω for CeCPE and CeBCPE, respectively. These fabricated electrodes were used as electrochemical sensors for cadmium ion estimation by optimizing the experimental parameters through differential pulse voltammetry. The optimized conditions included 10% modifier for CeCPE and 5% modifier for CeBCPE in 0.12 M HCl solution of pH 5 as supporting electrolyte at - 1.2 V deposition for 30 s in 0.01 to 10 mg L-1 linear cadmium solution range. Under these conditions, the limit of quantification (LOQ) of 0.368 mg L-1 and 0.005 mg L-1 was calculated for CeCPE and CeBCPE electrodes, respectively. The limit of detection (LOD) was calculated to be 0.121 mg L-1 and 0.002 mg L-1 for CeCPE and CeBCPE, respectively. All the experimental results indicated that electrodes fabricated from CeO2-Cu-BTC show better performance as compared to CeO2-based electrodes. Both these types of electrochemical sensors presented good repeatability and performance in the presence of interfering ions as well. From these findings, it can also be inferred that these electrochemical sensors can provide a simple and very sensitive method for approximation of toxic cadmium ions in aqueous solutions.

Assessment of heavy metals level in chicken with indeterminate analysis in localities of Lahore, Pakistan.

The poultry industry is a significant source of animal protein, vitamins, and minerals, particularly through the consumption of chicken meat. In order to conduct the study, 100 samples of liver, chicken feed, and drinking water were collected in nearby areas of Lahore. The investigation aims to detect the presence of specific heavy metals in the collected samples. For this purpose, atomic absorption spectroscopy (AAS) was used to detect heavy metals after proper preparation of the samples. The experimentally observed data were analyzed through a novel statistical approach known as neutrosophic statistics. It was observed that copper (Cu), zinc (Zn), and cadmium (Cd) were the most prominent metals detected with contamination above the safe limits (for chicken drinking water (Zn = 23.09±13.67 mg/L, Cu = 3.84±3.04 mg/L, Cd = 0.805±0.645 mg/L, Pb = 0.275±0.095 mg/L, As = 0.982±0.978 mg/L), for chicken feed (Zn = 2.705±0.715 mg/kg, Cu = 1.85±0.53 mg/kg, Cd = 3.065±1.185 mg/kg, Pb = 0.215±0.175 mg/kg, As = 0.68±0.22 mg/kg), and chicken's liver (Zn = 3.93±0.66 mg/kg, Cu = 1.2±0.52 mg/kg, Cd = 0.07±0.05 mg/kg, Pb = 0.805±0.775 mg/kg, As = 1.05±0.8 mg/kg)). Similarly, the statistical analysis leads that the findings emphasize the importance of monitoring and mitigating heavy metal contamination in the poultry industry to ensure the safety and quality of poultry products.

Opioid Exposure Differentially Impacts Esophageal Body Contraction Over the Lower Esophageal Sphincter.

BACKGROUND & AIMS: Studies with limited sample sizes have investigated association of chronic opioid use with motility disorders of esophagogastric junction and esophageal body peristalsis. Our aims were to use a large cohort of patients to assess (1) the impact of opioid exposure on clinical and manometric characteristics, and (2) the association of opioid exposure with higher long-term symptom burden. METHODS: Patients recruited from a tertiary medical center who underwent high-resolution manometry (HRM) between 2007 and 2018 were included. Demographics, opiate exposure, clinical symptoms, and HRM parameters were compared. Patient-Reported Outcomes Measurement Information System-Gastrointestinal swallowing domain (PROMIS-GI swallowing domain) and Eckardt score were administered via phone interviews in patients with hypercontractile esophagus (HE) or distal esophageal spasm (DES) to determine long-term symptom burden between opioid and nonopioid users. RESULTS: Our cohort included 4075 patients (869 with opiate exposure with median morphine milligram equivalent [interquartile range] of 30 [10-45]). Patients in the opioid group were significantly more likely to have dysphagia (65% vs 51%, P < .01) and diagnosis of DES (11% vs 5%, P < .01) and HE (9% vs 3%, P < .01). Partial opioid agonists were not associated with motility abnormalities. Patients on opioids had significantly higher symptom burden on median (interquartile range) follow-up of 8.9 years (5.8-10.4) post manometric diagnosis with median PROMIS-GI swallowing domain score of 21.5 (17-25) compared with the nonopioid group at 15 (9.8-21, P = .03). CONCLUSIONS: Nearly 2 of 3 patients with opioid exposure undergoing HRM have dysphagia and more than 25% of them with dysphagia as the primary symptom have a diagnosis of either DES or HE. Opioid users with spastic disorders have higher symptom burden long-term compared with nonopioid users.

Functional characterization of transcriptional activator gene SIARRI in tomato reveals its role in fruit growth and ripening.

Auxins regulate several characteristics of plant development and growth. Here, we characterized a new transcriptional activator SIARRI which binds specific DNA sequences and was revealed in Arabidopsis (ARR1). SIARRI acts as a two-component response regulator and its Arabidopsis homologous gene is AT3G16857. It belongs to the subfamily of type-B response regulators in the cytokinin signaling pathway. The study aimed to characterize the transgenic Micro-Tom plants by the overexpression of Solanum lycopersicum two-component response regulator ARR1. Overexpression of SIARRI results in a pleiotropic phenotype during fruit development and ripening. This study indicates that SIARRI is a primary regulator of leaf morphology and fruit development. Moreover, overexpressed plants showed variations in growth related to auxin as well as shorter hypocotyl elongation, enlarged leaf vascularization, and decreased apical dominance. The qRT-PCR investigation revealed that expression was downregulated at the breaker stage and high at Br+6 at various stages of fruit growth and ripening. In contrast to the fruit color, lycopene and ß-carotene concentrations in red-yellow overexpression line fruits were reduced significantly, and also slightly reduced in some red fruits. The quantity of ß-carotene in the transgenic fruits was lower than that of lycopene. This study showed that this gene might be a new transcriptional activator in fruit development and ripening. Furthermore, this study will provide new insights into tomato fruit ripening.

Microsomal glutathione transferase 1 controls metastasis and therapeutic response in melanoma.

While recent targeted and immunotherapies in malignant melanoma are encouraging, most patients acquire resistance, implicating a need to identify additional drug targets to improve outcomes. Recently, attention has been given to pathways that regulate redox homeostasis, especially the lipid peroxidase pathway that protects cells against ferroptosis. Here we identify microsomal glutathione S-transferase 1 (MGST1), a non-selenium-dependent glutathione peroxidase, as highly expressed in malignant and drug resistant melanomas and as a specific determinant of metastatic spread and therapeutic sensitivity. Loss of MGST1 in mouse and human melanoma enhanced cellular oxidative stress, and diminished glycolysis, oxidative phosphorylation, and pentose phosphate pathway. Gp100 activated pmel-1 T cells killed more Mgst1 KD than control melanoma cells and KD cells were more sensitive to cytotoxic anticancer drugs and ferroptotic cell death. When compared to control, mice bearing Mgst1 KD B16 tumors had more CD8+ T cell infiltration with reduced expression of inhibitory receptors and increased cytokine response, large reduction of lung metastases and enhanced survival. Targeting MGST1 alters the redox balance and limits metastases in melanoma, enhancing the therapeutic index for chemo- and immunotherapies.

Assessment of association between lower ureteric excision technique and oncological outcomes for upper urinary tract urothelial carcinoma: retrospective analysis from the Scottish Renal Cancer Consortium.

PURPOSE: Nephroureterectomy(NU) remains the gold-standard surgical option for the management of upper urinary tract urothelial carcinoma(UTUC). Controversy exists regarding the optimal excision technique of the lower ureter. We sought to compare post-UTUC bladder tumour recurrence across the Scottish Renal Cancer Consortium(SRCC). METHODS: Patients who underwent NU for UTUC across the SRCC 2012-2019 were identified. The impact of lower-end surgical technique along with T-stage, N-stage, tumour location and focality, positive surgical margin, pre-NU ureteroscopy, upper-end technique and adjuvant mitomycin C administration were assessed by Kaplan-Meier and Cox-regression. The primary outcome was intra-vesical recurrence-free survival (B-RFS). RESULTS: In 402 patients, the median follow-up was 29 months. The lower ureter was managed by open transvesical excision in 90 individuals, transurethral and laparoscopic dissection in 76, laparoscopic or open extra-vesical excision in 31 and 42 respectively, and transurethral dissection and pluck in 163. 114(28.4%) patients had a bladder recurrence during follow-up. There was no difference in B-RFS between lower-end techniques by Kaplan-Meier (p = 0.94). When all factors were taken into account by adjusted Cox-regression, preceding ureteroscopy (HR 2.65, p = 0.001), lower ureteric tumour location (HR 2.16, p = 0.02), previous bladder cancer (HR 1.75, p = 0.01) and male gender (HR 1.61, p = 0.03) were associated with B-RFS. CONCLUSION: These data suggest in appropriately selected patients, lower ureteric management technique does not affect B-RFS. Along with lower ureteric tumour location, male gender and previous bladder cancer, preceding ureteroscopy was associated with a higher recurrence rate following NU, and the indication for this should be carefully considered.

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis.

INTRODUCTION: Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. METHODS AND OBJECTIVE: We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. RESULTS: We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. CONCLUSION: Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation.

Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B-cell fate remain unclear. Here, we identified a role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells in which Dot1L was deleted showed aberrant differentiation and prematurely acquired plasma cell characteristics. Similar results were obtained when DOT1L was chemically inhibited in mature B cells in vitro. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L indirectly supports the repression of an anti-proliferative plasma cell differentiation program by maintaining the repression of Polycomb Repressor Complex 2 (PRC2) targets. Our findings show that DOT1L is a key modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B-cell naivety and GC B-cell differentiation.

Prediction of the COVID-19 transmission: a case study of Pakistan.

The world has suffered a lot from COVID-19 and is still on the verge of a new outbreak. The infected regions of coronavirus have been classified into four categories: SIRD model, (1) suspected, (2) infected, (3) recovered, and (4) deaths, where the COVID-19 transmission is evaluated using a stochastic model. A study in Pakistan modeled COVID-19 data using stochastic models like PRM and NBR. The findings were evaluated based on these models, as the country faces its third wave of the virus. Our study predicts COVID-19 casualties in Pakistan using a count data model. We've used a Poisson process, SIRD-type framework, and a stochastic model to find the solution. We took data from NCOC (National Command and Operation Center) website to choose the best prediction model based on all provinces of Pakistan, On the values of log L and AIC criteria. The best model among PRM and NBR is NBR because when over-dispersion happens; NBR is the best model for modelling the total suspected, infected, and recovered COVID-19 occurrences in Pakistan as it has the maximum log L and smallest AIC of the other count regression model. It was also observed that the active and critical cases positively and significantly affect COVID-19-related deaths in Pakistan using the NBR model.