Generation and Characterization of Ex Vivo Expanded Tumor-infiltrating Lymphocytes From Renal Cell Carcinoma Tumors for Adoptive Cell Therapy.

Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance antitumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC. Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion. Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel. The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion.

Study of morphology with assessment of expression of proliferation marker Ki67 antigen and P53 protein in lesions of gall bladder.

OBJECTIVE: To study the spectrum and distribution of histopathological changes and evaluate immunohistochemistry markers p53 protein and Ki67 antigen in various lesions of gall bladder. MATERIALS AND METHODS: A total of 804 consecutive gall bladder specimens were evaluated. Forty cases were selected for immunohistochemical analysis to evaluate expression of p53 and ki67 proliferation index, including 20 carcinoma gall bladder cases and 20 cases of inflammatory pathology associated with metaplasia, atypia, hyperplasia, dysplasia, and adenoma. p53 immunostaining was categorized as wild type and mutant type. ki67 of >20% was considered high expression. RESULTS: The majority of the gall bladder lesions were inflammatory in origin, most common being chronic cholecystitis. In the group of 20 gall bladder carcinoma cases, 65% were p53 mutant and the remaining 35% cases had a p53 wild-type immunophenotype. 55% cases showed high expression for ki67 labeling. However, significant correlation ( P < 0.05) was seen with lympho-vascular invasion. Among non-malignant lesions, normal/wild-type p53 expression was seen with increasing intensity and positivity in lesions with atypia and intra-epithelial neoplasms. Ki67 index also showed the same trend in all cases. CONCLUSIONS: p53 and ki-67 expression increases in inflammation, and further increment occurs in premalignant and malignant lesions of the gall bladder epithelium and can be used as a marker of aggression of histopathological lesions. The results emphasize the potential of Ki-67 and p53 as biomarkers of carcinogenesis in gall bladder carcinoma.

Efficacy of Fine-Needle Aspiration Cytology in Diagnosing Secretory Carcinoma of Salivary Gland: A Systematic Review and Meta-Analysis.

INTRODUCTION: The diagnosis of salivary gland secretory carcinoma (SC) in fine-needle aspiration specimens is challenging because its low-grade nature makes it difficult to differentiate it from various benign or malignant salivary gland neoplasms. Currently, the gold standard is demonstration of ETV6-NTRK3 fusion gene. However, the decision for ordering this costly molecular testing can be facilitated by the correct recognition of its cytomorphological features. The aim of the review was to determine the accuracy of fine-needle aspiration cytology (FNAC) in diagnosis of salivary gland SC. The secondary objective was to recognize varied cytomorphological patterns, characteristic features of SC and differentiate it from other neoplasms. METHODS: PubMed/MEDLINE, Science Direct, Embase, Cochrane review, and PROSPERO databases were searched for studies having the following key search terms: ("secretory carcinoma of salivary gland" OR "mammary analogue secretory carcinoma of salivary gland") AND ("Cytology" OR "Cytological features" OR "aspirate" OR "cytodiagnosis") published in the time frame of 2010 to June 2023. Studies reporting cytological features of the salivary gland tumors which were confirmed/diagnosed as SC on molecular investigation, were included in the systematic review. Finally, seventeen studies reporting a total of 45 cases were included in the metanalysis. RESULTS: The sensitivity of the FNAC in diagnosing SC in salivary gland is 27.7% (95% CI: 16.6-42.5%). The LR+ (positive likelihood ratio) was 0.654 (0.344-1.245), LR- (negative likelihood ratio) was 1.023 (0.538-1.946), and diagnostic odds ratio was 0.421 (0.129-1.374). The molecular testing and/or immunohistochemistry performed on cell block increased the diagnostic accuracy. CONCLUSION: Recognition of subtle cytomorphological patterns, i.e., papillary formation, clusters, and singly dispersed cells along with presence of fine intracytoplasmic vacuolations were the characteristic findings in majority of cases, confirmed with diagnostic molecular profiling. This may be helpful in identification of this rare entity with limited published literature and help in increasing diagnostic accuracy.

Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach.

Peripheral T-cell lymphoma (PTCL) is a clinically heterogeneous group that represents 10%-15% of all lymphomas. Despite improved genetic and molecular understanding, treatment outcomes for PTCL have not shown significant improvement. Although Janus kinase-2 (JAK2) plays an important role in myeloproliferative neoplasms, the critical role of JAK isoforms in mediating prosurvival signaling in PTCL cells is not well defined. Immunohistochemical analysis of PTCL tumors (n = 96) revealed high levels of constitutively active JAK3 (pJAK3) that significantly (p < 0.04) correlated with the activation state of its canonical substrate STAT3. Furthermore, constitutive activation of JAK3 and STAT3 positively correlated, at least in part, with an oncogenic tyrosine phosphatase PTPN11. Pharmacological inhibition of JAK3 but not JAK1/JAK2 significantly (p < 0.001) decreased PTCL proliferation, survival and STAT3 activation. A sharp contrast was observed in the pJAK3 positivity between ALK+ (85.7%) versus ALK-negative (10.0%) in human PTCL tumors and PTCL cell lines. Moreover, JAK3 and ALK reciprocally interacted in PTCL cells, forming a complex to possibly regulate STAT3 signaling. Finally, combined inhibition of JAK3 (by WHI-P154) and ALK (by crizotinib or alectinib) significantly (p < 0.01) decreased the survival of PTCL cells as compared to either agent alone by inhibiting STAT3 downstream signaling. Collectively, our findings establish that JAK3 is a therapeutic target for a subset of PTCL, and provide rationale for the clinical evaluation of JAK3 inhibitors combined with ALK-targeted therapy in PTCL.

Post-Translational Modifications in Histones and Their Role in Abiotic Stress Tolerance in Plants.

Abiotic stresses profoundly alter plant growth and development, resulting in yield losses. Plants have evolved adaptive mechanisms to combat these challenges, triggering intricate molecular responses to maintain tissue hydration and temperature stability during stress. A pivotal player in this defense is histone modification, governing gene expression in response to diverse environmental cues. Post-translational modifications (PTMs) of histone tails, including acetylation, phosphorylation, methylation, ubiquitination, and sumoylation, regulate transcription, DNA processes, and stress-related traits. This review comprehensively explores the world of PTMs of histones in plants and their vital role in imparting various abiotic stress tolerance in plants. Techniques, like chromatin immune precipitation (ChIP), ChIP-qPCR, mass spectrometry, and Cleavage Under Targets and Tag mentation, have unveiled the dynamic histone modification landscape within plant cells. The significance of PTMs in enhancing the plants' ability to cope with abiotic stresses has also been discussed. Recent advances in PTM research shed light on the molecular basis of stress tolerance in plants. Understanding the intricate proteome complexity due to various proteoforms/protein variants is a challenging task, but emerging single-cell resolution techniques may help to address such challenges. The review provides the future prospects aimed at harnessing the full potential of PTMs for improved plant responses under changing climate change.

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase.

In triple-negative breast cancer (TNBC) that relies on catabolism of amino acid glutamine, glutaminase (GLS) converts glutamine to glutamate, which facilitates glutathione synthesis by mediating the enrichment of intracellular cystine via xCT antiporter activity. To overcome chemo resistant TNBC, we have tested a strategy of disrupting cellular redox balance by inhibition of GLS and xCT by CB839 and Erastin, respectively. Key findings of our study include: 1. Dual metabolic inhibition (CB839+Erastin) led to significant increases of cellular superoxide level in both parent and chemo resistant TNBC cells, but superoxide level was distinctly lower in resistant cells. 2. Dual metabolic inhibition combined with doxorubicin or cisplatin induced significant apoptosis in TNBC cells and is associated with high degrees of GSH depletion. In vivo , dual metabolic inhibition plus cisplatin led to significant growth delay of chemo resistant human TNBC xenografts. 3. Ferroptosis is induced by doxorubicin (DOX) but not by cisplatin or paclitaxel. Addition of dual metabolic inhibition to DOX chemotherapy significantly enhanced ferroptotic cell death. 4. Significant changes in cellular metabolites concentration preceded transcriptome changes revealed by single cell RNA sequencing, underscoring the potential of capturing early changes in metabolites as pharmacodynamic markers of metabolic inhibitors. Here we demonstrated that 4-(3-[ 18 F]fluoropropyl)-L-glutamic acid ([ 18 F]FSPG) PET detected xCT blockade by Erastin or its analog in mice bearing human TNBC xenografts. In summary, our study provides compelling evidence for the therapeutic benefit and feasibility of non-invasive monitoring of dual metabolic blockade as a translational strategy to sensitize chemo resistant TNBC to cytotoxic chemotherapy.

Genetic and molecular understanding for the development of methionine-rich maize: a holistic approach.

Maize (Zea mays) is the most important coarse cereal utilized as a major energy source for animal feed and humans. However, maize grains are deficient in methionine, an essential amino acid required for proper growth and development. Synthetic methionine has been used in animal feed, which is costlier and leads to adverse health effects on end-users. Bio-fortification of maize for methionine is, therefore, the most sustainable and environmental friendly approach. The zein proteins are responsible for methionine deposition in the form of δ-zein, which are major seed storage proteins of maize kernel. The present review summarizes various aspects of methionine including its importance and requirement for different subjects, its role in animal growth and performance, regulation of methionine content in maize and its utilization in human food. This review gives insight into improvement strategies including the selection of natural high-methionine mutants, molecular modulation of maize seed storage proteins and target key enzymes for sulphur metabolism and its flux towards the methionine synthesis, expression of synthetic genes, modifying gene codon and promoters employing genetic engineering approaches to enhance its expression. The compiled information on methionine and essential amino acids linked Quantitative Trait Loci in maize and orthologs cereals will give insight into the hotspot-linked genomic regions across the diverse range of maize germplasm through meta-QTL studies. The detailed information about candidate genes will provide the opportunity to target specific regions for gene editing to enhance methionine content in maize. Overall, this review will be helpful for researchers to design appropriate strategies to develop high-methionine maize.

Characterization of phi112, a Molecular Marker Tightly Linked to the o2 Gene of Maize, and Its Utilization in Multiplex PCR for Differentiating Normal Maize from QPM.

Quality Protein Maize (QPM) contains higher amounts of essential amino acids lysine and tryptophan. The QPM phenotype is based on regulating zein protein synthesis by opaque2 transcription factor. Many gene modifiers act to optimize the amino acid content and agronomic performance. An SSR marker, phi112, is present upstream of the opaque2 DNA gene. Its analysis has shown the presence of transcription factor activity. The functional associations of opaque2 have been determined. The putative transcription factor binding at phi112 marked DNA was identified through computational analysis. The present study is a step towards understanding the intricate network of molecular interactions that fine-tune the QPM genotype to influence maize protein quality. In addition, a multiplex PCR assay for differentiation of QPM from normal maize is shown, which can be used for Quality Control at various stages of the QPM value chain.

Blockade of CCR1 induces a phenotypic shift in macrophages and triggers a favorable antilymphoma activity.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma, including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven-IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in vivo targeting of CCR1 with CCR1 antagonist BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.

18F-Fluciclovine PET Imaging of Glutaminase Inhibition in Breast Cancer Models.

Aggressive cancers such as triple-negative breast cancer (TNBC) avidly metabolize glutamine as a feature of their malignant phenotype. The conversion of glutamine to glutamate by the glutaminase enzyme represents the first and rate-limiting step of this pathway and a target for drug development. Indeed, a novel glutaminase inhibitor (GLSi) has been developed and tested in clinical trials but with limited success, suggesting the potential for a biomarker to select patients who could benefit from this novel therapy. Here, we studied a nonmetabolized amino acid analog, 18F-fluciclovine, as a PET imaging biomarker for detecting the pharmacodynamic response to GLSi. Methods: Uptake of 18F-fluciclovine into human breast cancer cells was studied in the presence and absence of inhibitors of glutamine transporters and GLSi. To allow 18F-fluciclovine PET to be performed on mice, citrate in the tracer formulation is replaced by phosphate-buffered saline. Mice bearing triple-negative breast cancer (TNBC) xenografts (HCC38, HCC1806, and MBA-MD-231) and estrogen receptor-positive breast cancer xenografts (MCF-7) were imaged with dynamic PET at baseline and after a 2-d treatment of GLSi (CB839) or vehicle. Kinetic analysis suggested reversible uptake of the tracer, and the distribution volume (VD) of 18F-fluciclovine was estimated by Logan plot analysis. Results: Our data showed that cellular uptake of 18F-fluciclovine is mediated by glutamine transporters. A significant increase in VD was observed after CB839 treatment in TNBC models exhibiting high glutaminase activity (HCC38 and HCC1806) but not in TNBC or MCF-7 exhibiting low glutaminase. Changes in VD were corroborated with changes in GLS activity measured in tumors treated with CB839 versus vehicle, as well as with changes in VD of 18F-(2S,R4)-fluoroglutamine, which we previously validated as a measure of cellular glutamine pool size. A moderate, albeit significant, decrease in 18F-FDG PET signal was observed in HCC1806 tumors after CB839 treatment. Conclusion: 18F-fluciclovine PET has potential to serve as a clinically translatable pharmacodynamic biomarker of GLSi.

Isobutanol production by combined in vivo and in vitro metabolic engineering.

The production of the biofuel, isobutanol, in E. coli faces limitations due to alcohol toxicity, product inhibition, product recovery, and long-term industrial feasibility. Here we demonstrate an approach of combining both in vivo with in vitro metabolic engineering to produce isobutanol. The in vivo production of α-ketoisovalerate (KIV) was conducted through CRISPR mediated integration of the KIV pathway in bicistronic design (BCD) in E. coli and inhibition of competitive valine pathway using CRISPRi technology. The subsequent in vitro conversion to isobutanol was carried out with engineered enzymes for 2-ketoacid decarboxylase (KIVD) and alcohol dehydrogenase (ADH). For the in vivo production of KIV and subsequent in vitro production of isobutanol, this two-step serial approach resulted in yields of 56% and 93%, productivities of 0.62 and 0.074 g L-1 h-1, and titers of 5.6 and 1.78 g L-1, respectively. Thus, this combined biosynthetic system can be used as a modular approach for producing important metabolites, like isobutanol, without the limitations associated with in vivo production using a consolidated bioprocess.

Determinants of respectful maternity care in India: A cross-sectional study.

Background: Respectful maternity care (RMC) is a basic right of all pregnant women. The study identifies the sociodemographic and economic factors influencing disrespect and abuse (D&A) faced by women during pregnancy, childbirth, and immediate postpartum period in India. Methodology: A cross-sectional study was conducted across six health facilities in three states of India from June 2019 to June 2020 among 401 women aged 18 years or more who had a live birth within the past 2 months of data collection. A validated structured interview schedule was used to capture data on sociodemographic and economic characteristics; antenatal, intranatal, and postnatal history; and incidences of D&A based on Bowser's seven domains of RMC. Ordered logistic regression was done to identify the determinant of high D&A. Results: The composite score of D&A ranged from 0 to 48 with a median interquartile range of 13 (9-17). All women faced one or the other kind of D&A. Women with the lowest food security (odds ratio [OR] = 3.3; 95% confidence interval: 1.6-6.7), who did not avail any antenatal care from the facility (OR = 1.9 [1.1-3.2]), and in the lowest wealth index (OR = 2.2 [1.3-3.7]) faced more D&A than those with high food security, more than two ANC services from same health facility, and in the high wealth index, respectively. Women who had low mobility score experienced lower D&A (OR = 0.5 [0.3-0.8]) as compared to the women with a high mobility score. Nonconsented care, nonconfidential care, and physical discomfort were the most common types of D&A. Conclusions: RMC is directly associated with socioeconomic status of women. Policy and program interventions are needed to address the inequity in health service care provision and expanding the social security net for women.

Dynamic Contrast-Enhanced MRI in the Abdomen of Mice with High Temporal and Spatial Resolution Using Stack-of-Stars Sampling and KWIC Reconstruction.

Application of quantitative dynamic contrast-enhanced (DCE) MRI in mouse models of abdominal cancer is challenging due to the effects of RF inhomogeneity, image corruption from rapid respiratory motion and the need for high spatial and temporal resolutions. Here we demonstrate a DCE protocol optimized for such applications. The method consists of three acquisitions: (1) actual flip-angle B1 mapping, (2) variable flip-angle T1 mapping and (3) acquisition of the DCE series using a motion-robust radial strategy with k-space weighted image contrast (KWIC) reconstruction. All three acquisitions employ spoiled radial imaging with stack-of-stars sampling (SoS) and golden-angle increments between the views. This scheme is shown to minimize artifacts due to respiratory motion while simultaneously facilitating view-sharing image reconstruction for the dynamic series. The method is demonstrated in a genetically engineered mouse model of pancreatic ductal adenocarcinoma and yielded mean perfusion parameters of Ktrans = 0.23 ± 0.14 min-1 and ve = 0.31 ± 0.17 (n = 22) over a wide range of tumor sizes. The SoS-sampled DCE method is shown to produce artifact-free images with good SNR leading to robust estimation of DCE parameters.

DWI Metrics Differentiating Benign Intraductal Papillary Mucinous Neoplasms from Invasive Pancreatic Cancer: A Study in GEM Models.

KPC (KrasG12D:Trp53R172H:Pdx1-Cre) and CKS (KrasG12D:Smad4L/L:Ptf1a-Cre) mice are genetically engineered mouse (GEM) models that capture features of human pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN), respectively. We compared these autochthonous tumors using quantitative imaging metrics from diffusion-weighted MRI (DW-MRI) and dynamic contrast enhanced (DCE)-MRI in reference to quantitative histological metrics including cell density, fibrosis, and microvasculature density. Our results revealed distinct DW-MRI metrics between the KPC vs. CKS model (mimicking human PDAC vs. IPMN lesion): the apparent diffusion coefficient (ADC) of CKS tumors is significantly higher than that of KPC, with little overlap (mean ± SD 2.24±0.2 vs. 1.66±0.2, p<10−10) despite intratumor and intertumor variability. Kurtosis index (KI) is also distinctively separated in the two models. DW imaging metrics are consistent with growth pattern, cell density, and the cystic nature of the CKS tumors. Coregistration of ex vivo ADC maps with H&E-stained sections allowed for regional comparison and showed a correlation between local cell density and ADC value. In conclusion, studies in GEM models demonstrate the potential utility of diffusion-weighted MRI metrics for distinguishing pancreatic cancer from benign pancreatic cysts such as IPMN.

Comparison of neonatal and maternal outcomes of anti-diabetic drugs in the treatment of gestational diabetes mellitus: Findings from Bayesian network meta-analysis.

The safety and efficacy of different anti-diabetic drugs are not clear because of the lack of sufficiently powered clinical trials. This network meta-analysis was conducted to compare the efficacy and safety of three anti-diabetic drugs (insulin, glyburide, and metformin), and rank them as per their efficiency to control glucose levels, pregnancy, and neonatal outcomes. The study design is a systematic review, meta-analysis, and network meta-analysis. After a systematic search of existing databases, 34 randomized controlled trials were selected for inclusion in the analysis. We did pairwise network meta-analysis to calculate standardized mean difference and odds ratio (OR) as the summary measures for numerical and dichotomous variables, respectively, by using random-effects model. Our key outcomes were incidence of neonatal hypoglycemia, respiratory distress syndrome, macrosomia, C-section, admission to neonatal intensive care unit (NICU) and mean differences in the birth weight of neonates, gestational age at birth, HbA1C levels, fasting blood sugar, large at gestational age, and post-prandial glucose. It was found that metformin significantly lowered the post-prandial levels of glucose as compared with both glyburide and insulin in pairwise analysis (SMD = 14.11 [23-4.8]; SMD = 22.45 [30-14]), respectively. There was a significant reduction in birth weights of babies whose mothers were administered metformin as compared with either glyburide or insulin. The proportion of neonates admission to NICU was significantly lower for metformin when compared with insulin [Log OR = 0.334 (0.0184, 0.6814))]. Large at gestational age was significantly lower for metformin as compared with both glyburide and insulin [log OR = 0.6882 (0.171, 1.329), log OR = 0.393 (0.00179, 0.8218)], respectively. Oral anti-diabetic drugs especially metformin performed better than both glyburide and insulin for all neonatal and maternal outcomes except that it significantly lowered the neonatal birth weight.

The HIV Latency Reversal Agent HODHBt Enhances NK Cell Effector and Memory-Like Functions by Increasing Interleukin-15-Mediated STAT Activation.

Elimination of human immunodeficiency virus (HIV) reservoirs is a critical endpoint to eradicate HIV. One therapeutic intervention against latent HIV is "shock and kill." This strategy is based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) with the consequent killing of the reactivated cell by either the cytopathic effect of HIV or the immune system. We have previously found that the small molecule 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) acts as an LRA by increasing signal transducer and activator of transcription (STAT) factor activation mediated by interleukin-15 (IL-15) in cells isolated from aviremic participants. The IL-15 superagonist N-803 is currently under clinical investigation to eliminate latent reservoirs. IL-15 and N-803 share similar mechanisms of action by promoting the activation of STATs and have shown some promise in preclinical models directed toward HIV eradication. In this work, we evaluated the ability of HODHBt to enhance IL-15 signaling in natural killer (NK) cells and the biological consequences associated with increased STAT activation in NK cell effector and memory-like functions. We showed that HODHBt increased IL-15-mediated STAT phosphorylation in NK cells, resulting in increases in the secretion of CXCL-10 and interferon gamma (IFN-γ) and the expression of cytotoxic proteins, including granzyme B, granzyme A, perforin, granulysin, FASL, and TRAIL. This increased cytotoxic profile results in increased cytotoxicity against HIV-infected cells and different tumor cell lines. HODHBt also improved the generation of cytokine-induced memory-like NK cells. Overall, our data demonstrate that enhancing the magnitude of IL-15 signaling with HODHBt favors NK cell cytotoxicity and memory-like generation, and thus, targeting this pathway could be further explored for HIV cure interventions. IMPORTANCE Several clinical trials targeting the HIV latent reservoir with LRAs have been completed. In spite of a lack of clinical benefit, they have been crucial to elucidate hurdles that "shock and kill" strategies have to overcome to promote an effective reduction of the latent reservoir to lead to a cure. These hurdles include low reactivation potential mediated by LRAs, the negative influence of some LRAs on the activity of natural killer and effector CD8 T cells, an increased resistance to apoptosis of latently infected cells, and an exhausted immune system due to chronic inflammation. To that end, finding therapeutic strategies that can overcome some of these challenges could improve the outcome of shock and kill strategies aimed at HIV eradication. Here, we show that the LRA HODHBt also improves IL-15-mediated NK cell effector and memory-like functions. As such, pharmacological enhancement of IL-15-mediated STAT activation can open new therapeutic avenues toward an HIV cure.

Narrowing down molecular targets for improving phosphorus-use efficiency in maize (Zea mays L.).

Conventional agricultural practices rely heavily on chemical fertilizers to boost production. Among the fertilizers, phosphatic fertilizers are copiously used to ameliorate low-phosphate availability in the soil. However, phosphorus-use efficiency (PUE) for major cereals, including maize, is less than 30%; resulting in more than half of the applied phosphate being lost to the environment. Rock phosphate reserves are finite and predicted to exhaust in near future with the current rate of consumption. Thus, the dependence of modern agriculture on phosphatic fertilizers poses major food security and sustainability challenges. Strategies to optimize and improve PUE, like genetic interventions to develop high PUE cultivars, could have a major impact in this area. Here, we present the current understanding and recent advances in the biological phenomenon of phosphate uptake, translocation, and adaptive responses of plants under phosphate deficiency, with special reference to maize. Maize is one of the most important cereal crops that is cultivated globally under diverse agro-climatic conditions. It is an industrial, feed and food crop with multifarious uses and a fast-rising global demand and consumption. The interesting aspects of diversity in the root system architecture traits, the interplay between signaling pathways contributing to PUE, and an in-depth discussion on promising candidate genes for improving PUE in maize are elaborated.

Relative contribution of susceptibility weighted imaging, compared to conventional MRI, in the detection of common bile-duct calculi.

PURPOSE We aimed to evaluate the relative contribution of susceptibility weighted imaging (SWI) in the detection of common bile-duct (CBD) stones in comparison to the conventional MRI protocol containing magnetic resonance cholangiopancreatography (MRCP), balanced turbo field echo (BTFE), and T2-weighted spin-echo imaging techniques. METHODS MRI data containing MRCP, BTFE, T2-weighted imaging, and abdominal SWI were independently evaluated by 2 sets of experienced radiologists in 44 patients with confirmed CBD stones. Endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound where available, was used as the reference gold standard. Evaluation was performed for the visualization of CBD stones in each of the MRI techniques. Relative contribution of SWI was classified into one of four categories for each case: (1) no contribution to CBD stone visualization; (2) same as conventional techniques; (3) improved diagnostic confidence; and (4) critical for diagnosis. Stone size was also assessed. RESULTS Inter-rater agreement coefficient for CBD stone visualization was found to be "good" in MRCP (0.77), "very good" in SWI (0.94) and BTFE (0.84), and moderate in T2-weighted imaging (0.54). CBD stones were visualized with SWI in 86.4% and 82%, with MRCP in 70.5% and 70.5% cases, with BTFE in 73% and 61.4% cases, with T2-weighted imaging in 45.5% and 52.3% cases by reviewers 1 and 2, respectively. SWI did not contribute to CBD stone visualization in 2.3% (1/44); was the same as conventional techniques in 31.8% (14/44) cases; improved diagnostic confidence in 34.1%; and was critical for diagnosis in 20.5% cases. CONCLUSION SWI has the potential to serve as a strong adjunct to conventional MRI protocols used for CBD stone evaluation with very small scan-time penalty.

Role of intra-tumoral vasculature imaging features on susceptibility weighted imaging in differentiating primary central nervous system lymphoma from glioblastoma: a multiparametric comparison with pathological validation.

PURPOSE: Primary objective of this study was to retrospectively evaluate the potential of a range of qualitative and quantitative multiparametric features assessed on T2, post-contrast T1, DWI, DCE-MRI, and susceptibility-weighted-imaging (SWI) in differentiating evenly sampled cohort of primary-central-nervous-system-lymphoma (PCNSL) vs glioblastoma (GB) with pathological validation. METHODS: The study included MRI-data of histopathologically confirmed ninety-five GB and PCNSL patients scanned at 3.0 T MRI. A total of six qualitative features (three from T2 and post-contrast T1, three from SWI: thin-linear-uninterrupted-intra-tumoral-vasculature, broken-intra-tumoral-microvasculature, hemorrhage) were analyzed by three independent radiologists. Ten quantitative features from DWI and DCE-MRI were computed using in-house-developed algorithms. For qualitative features, Cohen's Kappa-interrater-variability-analysis was performed. Z-test and independent t-tests were performed to find significant qualitative and quantitative features respectively. Logistic-regression (LR) classifiers were implemented for evaluating performance of individual and various combinations of features in differentiating PCNSL vs GB. Performance evaluation was done via ROC-analysis. Pathological validation was performed to verify disintegration of vessel walls in GB and rim of viable neoplastic lymphoid cells with angiocentric-pattern in PCNSL. RESULTS: Three qualitative SWI features and four quantitative DCE-MRI features (rCBVcorr, Kep, Ve, and necrosis-volume-percentage) were significantly different (p < 0.05) between PCNSL and GB. Best diagnostic performance was observed with LR classifier using SWI features (AUC-0.99). The inclusion of quantitative features with SWI feature did not improve the differentiation accuracy. CONCLUSIONS: The combination of three qualitative SWI features using LR provided the highest accuracy in differentiating PCNSL and GB. Thin-linear-uninterrupted-intra-tumoral-vasculature in PCNSL and broken-intra-tumoral-microvasculature with hemorrhage in GB are the major contributors to the differentiation.