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1.
Int J Biol Macromol ; : 132704, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38825283

ABSTRACT

HOXA9 transcription factor is expressed in hematopoietic stem cells and is involved in the regulation of their differentiation and maturation to various blood cells. HOXA9 is linked to various leukemia and is a marker for poor prognosis of acute myeloid leukemia (AML). This protein has a conserved DNA-binding homeodomain and a transactivation domain. We show that this N-terminal transactivation domain is intrinsically disordered and inhibits DNA-binding by the homeodomain. Using NMR spectroscopy and molecular dynamics simulation, we show that the hexapeptide 197AANWLH202 in the disordered region transiently occludes the DNA-binding interface. The hexapeptide also forms a rigid segment, as determined by NMR dynamics, in an otherwise flexible disordered region. Interestingly, this hexapeptide is known to mediate the interaction of HOXA9 and its TALE partner proteins, such as PBX1, and help in cooperative DNA binding. Mutation of tryptophan to alanine in the hexapeptide abrogates the DNA-binding auto-inhibition. We propose that the disordered transactivation region plays a dual role in the regulation of HOXA9 function. In the absence of TALE partners, it inhibits DNA binding, and in the presence of TALE partners it interacts with the TALE protein and facilitates the cooperative DNA binding by the HOX-TALE complex.

2.
Cureus ; 16(4): e57472, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38699117

ABSTRACT

Introduction With the growing acceptance of transgender individuals, the number of gender affirmation surgeries has increased. Transgender individuals face elevated depression rates, leading to an increase in suicide ideation and attempts. This study evaluates the risk of suicide or self-harm associated with gender affirmation procedures. Methods This retrospective study utilized de-identified patient data from the TriNetX (TriNetX, LLC, Cambridge, MA) database, involving 56 United States healthcare organizations and over 90 million patients. The study involved four cohorts: cohort A, adults aged 18-60 who had gender-affirming surgery and an emergency visit (N = 1,501); cohort B, control group of adults with emergency visits but no gender-affirming surgery (N = 15,608,363); and cohort C, control group of adults with emergency visits, tubal ligation or vasectomy, but no gender-affirming surgery (N = 142,093). Propensity matching was applied to cohorts A and C. Data from February 4, 2003, to February 4, 2023, were analyzed to examine suicide attempts, death, self-harm, and post-traumatic stress disorder (PTSD) within five years of the index event. A secondary analysis involving a control group with pharyngitis, referred to as cohort D, was conducted to validate the results from cohort C. Results Individuals who underwent gender-affirming surgery had a 12.12-fold higher suicide attempt risk than those who did not (3.47% vs. 0.29%, RR 95% CI 9.20-15.96, p < 0.0001). Compared to the tubal ligation/vasectomy controls, the risk was 5.03-fold higher before propensity matching and remained significant at 4.71-fold after matching (3.50% vs. 0.74%, RR 95% CI 2.46-9.024, p < 0.0001) for the gender affirmation patients with similar results with the pharyngitis controls. Conclusion Gender-affirming surgery is significantly associated with elevated suicide attempt risks, underlining the necessity for comprehensive post-procedure psychiatric support.

3.
Plant Cell ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701340

ABSTRACT

Improving photosynthesis, the fundamental process by which plants convert light energy into chemical energy, is a key area of research with great potential for enhancing sustainable agricultural productivity and addressing global food security challenges. This perspective delves into the latest advancements and approaches aimed at optimizing photosynthetic efficiency. Our discussion encompasses the entire process, beginning with light harvesting and its regulation and progressing through the bottleneck of electron transfer. We then delve into the carbon reactions of photosynthesis, focusing on strategies targeting the enzymes of the Calvin-Benson-Bassham (CBB) cycle. Additionally, we explore methods to increase CO2 concentration near the Rubisco, the enzyme responsible for the first step of CBB cycle, drawing inspiration from various photosynthetic organisms, and conclude this section by examining ways to enhance CO2 delivery into leaves. Moving beyond individual processes, we discuss two approaches to identifying key targets for photosynthesis improvement: systems modeling and the study of natural variation. Finally, we revisit some of the strategies mentioned above to provide a holistic view of the improvements, analyzing their impact on nitrogen use efficiency and on canopy photosynthesis.

5.
Molecules ; 29(9)2024 May 05.
Article in English | MEDLINE | ID: mdl-38731640

ABSTRACT

We modified C3-symmetric benzene-1,3,5-tris-amide (BTA) by introducing flexible linkers in order to generate an N-centered BTA (N-BTA) molecule. The N-BTA compound formed gels in alcohols and aqueous mixtures of high-polar solvents. Rheological studies showed that the DMSO/water (1:1, v/v) gels were mechanically stronger compared to other gels, and a similar trend was observed for thermal stability. Powder X-ray analysis of the xerogel obtained from various aqueous gels revealed that the packing modes of the gelators in these systems were similar. The stimuli-responsive properties of the N-BTA towards sodium/potassium salts indicated that the gel network collapsed in the presence of more nucleophilic anions such as cyanide, fluoride, and chloride salts at the MGC, but the gel network was intact when in contact with nitrate, sulphate, acetate, bromide, and iodide salts, indicating the anion-responsive properties of N-BTA gels. Anion-induced gel formation was observed for less nucleophilic anions below the MGC of N-BTA. The ability of N-BTA gels to act as an adsorbent for hazardous anionic and cationic dyes in water was evaluated. The results indicated that the ethanolic gels of N-BTA successfully absorbed methylene blue and methyl orange dyes from water. This work demonstrates the potential of the N-BTA gelator to act as a stimuli-responsive material and a promising candidate for water purification.

6.
Cureus ; 16(4): e58301, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38752083

ABSTRACT

Background The purpose of this in vitro investigation was to evaluate the impact of five distinct commercial mouthwashes on the development of Candida albicans that had been adhered to heat-cured acrylic resin sheets. Methods This in vitro investigation was carried out at the MES Medical College's Microbiology Department in Perinthalmanna, Kerala, India. A total of 72 heat-cured acrylic resin sheets, size 10 × 10 × 2 mm, were fabricated. After disinfection, all 72 acrylic sheets were placed in a flask containing a suspension of the standard strain of Candida species (American Type Culture Collection) and incubated at 37ºC for 24 hours. Then, the acrylic sheets were randomly divided into six groups, with each group containing 12 acrylic sheets. Group 1 was the control group to which no mouthwash was added. In group 2, Colgate Plax was added. In group 3, Hiora Himalaya was added. In group 4, Oral B was added. In group 5, Listerine was added. In group 6, Pepsodent was added. Colony-forming units (CFUs) were assessed using a colony counter every six, 24, 48, and 120 hours. After obtaining the pH and CFU of all 72 specimens, software known as the Statistical Package for Social Sciences (SPSS) (IBM Corp., Armonk, NY) was used to analyze the data. Results Candida albicans adhered to heat-cured denture base acrylic resin sheets differed significantly in response to commercially available mouthwashes (Oral B, Colgate Plax, and Pepsodent) and non-commercial mouthwashes (Hiora Himalaya and Listerine) that contained cetylpyridinium chloride. Conclusions Compared to other mouthwashes that do not contain cetylpyridinium chloride (Listerine and Hiora Himalaya), mouthwashes with cetylpyridinium chloride as the active ingredient (Oral B, Pepsodent, and Colgate Plax) have shown good antifungal properties against the adhering Candida albicans on denture base resin.

7.
Laryngoscope ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38771083

ABSTRACT

Medullary thyroid carcinoma (MTC) comprises less than 5% of thyroid cancers but is responsible for over 10% of deaths related to thyroid cancer. Regional lymph node metastasis is common and associated with mortality, thus total thyroidectomy with central compartment lymph node dissection is the standard surgical treatment for MTC. In this best practice submission, we aim to review the existing literature and determine whether calcitonin levels can serve as a reliable method for risk-stratifying MTC without overt lymph node involvement.

8.
Nat Commun ; 15(1): 4653, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38821942

ABSTRACT

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Genetic Heterogeneity , Lung Neoplasms , Mice, Inbred NOD , Mice, SCID , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Animals , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Female , Exome Sequencing , Genomics/methods , Male , Xenograft Model Antitumor Assays , Heterografts , Disease Models, Animal , Aged , Middle Aged
9.
Sci Rep ; 14(1): 12500, 2024 05 31.
Article in English | MEDLINE | ID: mdl-38822009

ABSTRACT

Fusarium wilt, caused by (Fusarium udum Butler), is a significant threat to pigeonpea crops worldwide, leading to substantial yield losses. Traditional approaches like fungicides and resistant cultivars are not practical due to the persistent and evolving nature of the pathogen. Therefore, native biocontrol agents are considered to be more sustainable solution, as they adapt well to local soil and climatic conditions. In this study, five isolates of F. udum infecting pigeonpea were isolated from various cultivars and characterized morphologically and molecularly. The isolate from the ICP 8858 cultivar displayed the highest virulence of 90%. Besides, 100 endophytic bacteria, 100 rhizosphere bacteria and three Trichoderma spp. were isolated and tested against F. udum isolated from ICP 8858 under in vitro conditions. Out of the 200 bacteria tested, nine showed highest inhibition, including Rb-4 (Bacillus sp.), Rb-11 (B. subtilis), Rb-14 (B. megaterium), Rb-18 (B. subtilis), Rb-19 (B. velezensis), Eb-8 (Bacillus sp.), Eb-11 (B. subtilis), Eb-13 (P. aeruginosa), and Eb-21 (P. aeruginosa). Similarly, Trichoderma spp. were identified as T. harzianum, T. asperellum and Trichoderma sp. Notably, Rb-18 (B. subtilis) and Eb-21 (P. aeruginosa) exhibited promising characteristics such as the production of hydrogen cyanide (HCN), cellulase, siderophores, ammonia and nutrient solubilization. Furthermore, treating pigeonpea seedlings with these beneficial microorganisms led to increased levels of key enzymes (POD, PPO, and PAL) associated with resistance to Fusarium wilt, compared to untreated controls. In field trials conducted for four seasons, the application of these potential biocontrol agents as seed treatments on the susceptible ICP2376 cultivar led to the lowest disease incidence. Specifically, treatments T2 (33.33) (P. aeruginosa) and T3 (35.41) (T. harzianium) exhibited the lowest disease incidence, followed by T6 (36.5) (Carbendizim), T1 (36.66) (B. subtilis), T4 (52.91) (T. asperellum) and T5 (53.33) (Trichoderma sp.). Results of this study revealed that, P. aeruginosa (Eb-21), B. subtilis (Rb-18) and T. harzianum can be used for plant growth promotion and management of Fusarium wilt of pigeonpea.


Subject(s)
Cajanus , Fusarium , Plant Diseases , Fusarium/pathogenicity , Cajanus/microbiology , Plant Diseases/microbiology , Plant Diseases/prevention & control , Biological Control Agents , Trichoderma/physiology , Rhizosphere , Soil Microbiology , Pest Control, Biological/methods
10.
J Water Health ; 22(3): 467-486, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38557565

ABSTRACT

Pacific Island Countries (PICs) collectively have the lowest rates of access to safely managed or basic drinking water and sanitation globally. They are also the least urbanised, have dynamic socioeconomic and increasing climate-linked challenges. Community-based water managers need to respond to variability in water availability and quality caused by a range of hazards. Water Safety Planning (WSP), a widely adopted approach to assessing water supply, offers a risk-based approach to mitigating both existing and future hazards. WSP is adaptable, and making modifications to prescribed WSP to adapt it to the local context is common practice. Within the Pacific Community Water Management Plus research project, we used formative research and co-development processes to understand existing local modifications, whether further modifications are required, and, to develop additional modifications to WSP in Fiji, Vanuatu and Solomon Islands. The types of additional local modifications we recommend reflect the unique context of PICs, including adjusting for community management of water supplies and required collective action, community governance systems, levels of social cohesion in communities, and preferred adult-learning pedagogies. Incorporating modifications that address these factors into future WSP will improve the likelihood of sustained and safe community water services in Pacific and similar contexts.


Subject(s)
Rural Population , Humans , Adult , Pacific Islands , Vanuatu , Fiji , Melanesia
11.
Cureus ; 16(2): e55296, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38558674

ABSTRACT

Pilar cysts are derived from the outer layer of the root sheath of hair follicles. They were conventionally thought to arise from hair-bearing skin like the scalp. However, this notion has been refuted recently. Pilar cysts of the hand are extremely rare, with only a few case reports in the literature. We report the case of a 40-year-old male patient, with no known medical co-morbidities, who presented with a swelling over his left thumb. It was occasionally painful, and caused difficulty in grasping objects. Physical examination revealed a 2.5 x 1.5 cm swelling over the volar aspect of the thumb, at the level of the proximal phalanx. MRI revealed the presence of a well-defined cystic lesion superficial to the flexor tendons. The possibility of an epidermal cyst was considered, and the patient was advised surgery in view of his symptoms and progression in the size of the swelling. He underwent excision of the lesion along with a segment of adherent skin. Histopathological examination of the lesion revealed the presence of a pilar cyst. The patient did not have recurrence of symptoms following surgery, and was found to be doing well at the three-year follow-up. This case report urges a re-thinking of the possible origins of pilar cysts from atypical locations.

12.
J Homosex ; : 1-24, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38564428

ABSTRACT

Focusing on the Malayalam film Ka Bodyscapes (2016), this article attempts to historically trace and critically engage with the representations of gay sexuality in Malayalam cinema from the South Indian state of Kerala. It interrogates how Ka Bodyscapes brought to the forefront hitherto unexplored visual dynamics of the gay male body and homoeroticism on screen while troubling the heterosexual dynamics of the Malayalam film industry. By situating this film within the history of representation of male homosexuality in Malayalam cinema and the changing regimes of queer politics and feminist interventions in Kerala in the last decade, the article argues how the film's radical visual representation of gay sexuality at the intersection of caste and religion problematizes the heterosexual family/state, thereby challenging the patriarchal masculinity that marginalizes women and sexual minorities in Kerala.

13.
Nat Commun ; 15(1): 3167, 2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38609367

ABSTRACT

Heme has a critical role in the chemical framework of the cell as an essential protein cofactor and signaling molecule that controls diverse processes and molecular interactions. Using a phylogenomics-based approach and complementary structural techniques, we identify a family of dimeric hemoproteins comprising a domain of unknown function DUF2470. The heme iron is axially coordinated by two zinc-bound histidine residues, forming a distinct two-fold symmetric zinc-histidine-iron-histidine-zinc site. Together with structure-guided in vitro and in vivo experiments, we further demonstrate the existence of a functional link between heme binding by Dri1 (Domain related to iron 1, formerly ssr1698) and post-translational regulation of succinate dehydrogenase in the cyanobacterium Synechocystis, suggesting an iron-dependent regulatory link between photosynthesis and respiration. Given the ubiquity of proteins containing homologous domains and connections to heme metabolism across eukaryotes and prokaryotes, we propose that DRI (Domain Related to Iron; formerly DUF2470) functions at the molecular level as a heme-dependent regulatory domain.


Subject(s)
Hemeproteins , Synechocystis , Heme , Zinc , Histidine , Hemeproteins/genetics , Synechocystis/genetics , Carbon , Iron
14.
Sci Rep ; 14(1): 9347, 2024 04 23.
Article in English | MEDLINE | ID: mdl-38654096

ABSTRACT

Breast cancer, a leading cause of female mortality due to delayed detection owing to asymptomatic nature and limited early diagnostic tools, was investigated using a multi-modal approach. Plasma-derived small EVs from breast cancer patients (BrCa, n = 74) and healthy controls (HC, n = 30) were analyzed. Small EVs (n = 104), isolated through chemical precipitation, underwent characterization via transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Validation involved antibody-based tests (TSG101, CD9, CD81, CD63). Infrared spectra of small EVs were obtained, revealing significant differences in lipid acyl chains, particularly in the C-H stretching of CH3. The study focused on the lipid region (3050-2900 cm-1), identifying peaks (3015 cm-1, 2960 cm-1, 2929 cm-1) as distinctive lipid characteristics. Spectroscopic lipid-to-lipid ratios [(I3015/I2929), (I2960/I2929)] emerged as prominent breast cancer markers. Exploration of protein, nucleic acid, and carbohydrate ratios indicated variations in alpha helices, asymmetric C-H stretching vibrations, and C-O stretching at 1033 cm-1. Principal component analysis (PCA) successfully differentiated BrCa and HC small EVs, and heatmap analysis and receiver operating characteristic (ROC) curve evaluations underscored the discriminatory power of lipid ratios. Notably, (I2960/I2929) exhibited 100% sensitivity and specificity, highlighting its potential as a robust BrCa sEV marker for breast cancer detection.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms , Extracellular Vesicles , Lipids , Spectrophotometry, Infrared , Humans , Breast Neoplasms/diagnosis , Female , Extracellular Vesicles/metabolism , Extracellular Vesicles/chemistry , Lipids/chemistry , Lipids/analysis , Spectrophotometry, Infrared/methods , Middle Aged , Adult , Aged
15.
Front Plant Sci ; 15: 1333249, 2024.
Article in English | MEDLINE | ID: mdl-38628362

ABSTRACT

Biostimulants (Bio-effectors, BEs) comprise plant growth-promoting microorganisms and active natural substances that promote plant nutrient-acquisition, stress resilience, growth, crop quality and yield. Unfortunately, the effectiveness of BEs, particularly under field conditions, appears highly variable and poorly quantified. Using random model meta-analyses tools, we summarize the effects of 107 BE treatments on the performance of major crops, mainly conducted within the EU-funded project BIOFECTOR with a focus on phosphorus (P) nutrition, over five years. Our analyses comprised 94 controlled pot and 47 field experiments under different geoclimatic conditions, with variable stress levels across European countries and Israel. The results show an average growth/yield increase by 9.3% (n=945), with substantial differences between crops (tomato > maize > wheat) and growth conditions (controlled nursery + field (Seed germination and nursery under controlled conditions and young plants transplanted to the field) > controlled > field). Average crop growth responses were independent of BE type, P fertilizer type, soil pH and plant-available soil P (water-P, Olsen-P or Calcium acetate lactate-P). BE effectiveness profited from manure and other organic fertilizers, increasing soil pH and presence of abiotic stresses (cold, drought/heat or salinity). Systematic meta-studies based on published literature commonly face the inherent problem of publication bias where the most suspected form is the selective publication of statistically significant results. In this meta-analysis, however, the results obtained from all experiments within the project are included. Therefore, it is free of publication bias. In contrast to reviews of published literature, our unique study design is based on a common standardized protocol which applies to all experiments conducted within the project to reduce sources of variability. Based on data of crop growth, yield and P acquisition, we conclude that application of BEs can save fertilizer resources in the future, but the efficiency of BE application depends on cropping systems and environments.

16.
Front Microbiol ; 15: 1320812, 2024.
Article in English | MEDLINE | ID: mdl-38567078

ABSTRACT

Host-microbe dynamics are of increasing interest in marine research due to their role in host health and productivity. Changes in the shell microbiome of American lobsters have been associated with epizootic shell disease, a syndrome that is spreading northwards across the eastern U.S. and Canadian Atlantic coast. This study analyzed differences in alpha and beta diversity, as well as differentially abundant taxa, in the shell-associated bacterial community of apparently healthy lobsters from four lobster fishing areas (LFAs) in Atlantic Canada. Over 180 lobsters from New Brunswick, Nova Scotia and Prince Edward Island (PEI) were sampled during seven sampling events over four sampling months. The bacterial community was identified using novel PacBio long-read sequencing, while alpha and beta diversity parameters were analyzed using linear regression models and weighted UniFrac distances. The bacterial richness, diversity and evenness differed by sampling location, sampling month, and molt stage, but not by lobster sex or size, nor sampling depth. Similarly, based on LFA, sampling month, year and lobster molt stage, the shell microbiome differed in microbial community composition with up to 34 out of 162 taxa differing significantly in abundance between sampling groups. This large-scale microbial survey suggests that the shell microbial diversity of apparently healthy lobsters is influenced by spatial and temporal factors such as geographic location, as well as the length of time the carapace is exposed to the surrounding seawater.

17.
Indian J Community Med ; 49(2): 322-333, 2024.
Article in English | MEDLINE | ID: mdl-38665453

ABSTRACT

Background: Undernutrition is an important public health problem affecting one-third of under five-year-old children in India. Objectives: To assess the nutritional status of under five-year-old children along with child feeding practices. Materials and Methods: We adopted a systematic sampling procedure to carry out this community-based, cross-sectional study in all the districts of Haryana. Data was collected on socioeconomic and demographic particulars along with anthropometric measurements. Analysis was done using SPSS Windows 23. Results: The overall prevalence of stunting, underweight, and wasting was 34%, 27.5%, and 11%, while that of severe undernutrition was 11%, 8%, and 3%, respectively. The odds of underweight were significantly higher among children of the Muslim religion, children of scheduled caste, children of illiterate mothers, lower per capita income, HHs without electricity, landless HHs, low birth weight, no ANC care, and those early ages at complementary feeding. Stunting was significantly higher among children whose mothers were illiterate, children whose fathers were laborers, among landless HHs, with no separate kitchen and lower birth weight, while wasting was higher among children of Muslim religion, children of scheduled caste, with no sanitary latrine facility, low-birth-weight children and early initiation of complementary feeding. Conclusions: Undernutrition is observed to be associated with religion, community, education of mother, per capita income, land holding status, birth weight, and age at complementary feeding. Thus, improving maternal nutrition can improve birth weight, improving maternal knowledge about child feeding, and the household's socio-economic status may improve the nutritional status of children.

18.
J Am Chem Soc ; 146(17): 11648-11656, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38629317

ABSTRACT

Imidazolones represent an important class of heterocycles present in a wide range of pharmaceuticals, metabolites, and bioactive natural products and serve as the active chromophore in green fluorescent protein. Recently, imidazolones have received attention for their ability to act as a nonaromatic amide bond bioisotere which improves pharmacological properties. Herein, we present a tandem amidine installation and cyclization with an adjacent ester to yield (4H)-imidazolone products. Using amino acid building blocks, we can access the first examples of α-chiral imidazolones that have been previously inaccessible. Additionally, our method is amenable to on-resin installation which can be seamlessly integrated into existing solid-phase peptide synthesis protocols. Finally, we show that peptide imidazolones are potent cis-amide bond surrogates that preorganize linear peptides for head-to-tail macrocyclization. This work represents the first general approach to the backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.


Subject(s)
Amides , Imidazoles , Peptides , Imidazoles/chemistry , Imidazoles/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Amides/chemistry , Cyclization , Stereoisomerism , Molecular Structure
19.
Int J Mol Sci ; 25(7)2024 Mar 31.
Article in English | MEDLINE | ID: mdl-38612722

ABSTRACT

Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of protein disulfide isomerase 4 (PDIA-4); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFß-signaling, and inhibition of TGFß-signaling suppressed EndMT in PDIA-4-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions.


Subject(s)
Endothelial Cells , Protein Disulfide-Isomerases , Protein Disulfide-Isomerases/genetics , Apoptosis , Autophagy , Transforming Growth Factor beta
20.
J Mol Histol ; 55(3): 303-315, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38613589

ABSTRACT

BACKGROUND: The prevalence of TNBC in India is higher compared to western countries. There is a multitude of biomarkers associated with different clinical outcomes of TNBC with contradictory reports. Identification of a set of specific biomarkers from the very many number of proteins reported in the literature to predict prognosis of TNBC is an urgent clinical need. METHODOLOGY: A systematic review of key molecular biomarkers in cohort studies that have been investigated for their role in breast cancer prognosis was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. A meta-analysis was used to evaluate their pooled hazard ratio (HR) and the corresponding 95% confidence interval (95% CI) statistically. Immunohistochemical characterization of the meta-analyzed markers were performed in a cohort of 200 retrospective TNBC and 100 non TNBC patient tissues. Kaplan-Meier plot were used to evaluate disease free survival (DFS), and overall survival (OS). Cox regression models were used to evaluate predictors of DFS and OS. RESULTS: Using a meta-analytical approach, we consolidated the biomarker signatures associated with survival outcomes in breast cancers. The promising markers that emerged for the prediction of DFS and OS included E-Cadherin, Survivin, p53, MTA1, HIF1A, CD133, Vimentin and CK5/6. Evaluation of these markers in tumor tissue revealed that subcellular localization of p53, MTA1 and HIF1A had a significant association in predicting TNBC prognosis. Kaplan Meier plot revealed that p53 (OS p = 0.007, DFS p = 0.004), HIF 1 A (OS p = 0.054, DFS p = 0.009) and MTA1 (OS p = 0.043, DFS = p = 0.001) expression in the primary tumor tissue were found to be significantly correlated with poor OS and DFS, whereas expression of Survivin (DFS p = 0.024) and E Cadherin (DFS p = 0.027) correlated with DFS alone in TNBC. Univariate analysis revealed that p53, HIF1A and MTA1 could be independent prognostic markers. CONCLUSION: Our study suggests cytoplasmic over expression of HIF1A, nuclear over expression of MTA1 and mutated p53 in the primary tumor tissue of TNBC have significance as markers predicting survival of TNBC patients.


Subject(s)
Biomarkers, Tumor , Histone Deacetylases , Hypoxia-Inducible Factor 1, alpha Subunit , Repressor Proteins , Trans-Activators , Triple Negative Breast Neoplasms , Tumor Suppressor Protein p53 , Humans , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , Tumor Suppressor Protein p53/metabolism , Repressor Proteins/metabolism , Biomarkers, Tumor/metabolism , Female , Trans-Activators/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Histone Deacetylases/metabolism , Histone Deacetylases/genetics , Prognosis , Kaplan-Meier Estimate
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