Identification of potent BRD4-BD1 inhibitors using classical and steered molecular dynamics based free energy analysis.

In the present work a combination of traditional and steered molecular dynamics based techniques were employed to identify potential inhibitors against the human BRD4 protein (BRD4- BD1); an established drug target for multiple illnesses including various malignancies. Quinoline derivatives that were synthesized in-house were tested for their potential as new BRD4-BD1 inhibitors. Initially molecular docking experiments were performed to determine the binding poses of BRD4-BD1 inhibitors. To learn more about the thermodynamics of inhibitor binding to the BRD4-BD1 active site, the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) free energy calculations were conducted afterwards. The findings of the MM-PBSA analysis were further reinforced by performing steered umbrella sampling simulations which revealed crucial details about the binding/unbinding process of the most potent quinoline derivatives at the BRD4-BD1 active site. We report a novel quinoline derivative which can be developed into a fully functional BRD4-BD1 inhibitor after experimental validation. The identified compound (4 g) shows better properties than the standard BRD4-BD1 inhibitors considered in the study. The study also highlights the crucial role of Gln78, Phe79, Trp81, Pro82, Phe83, Gln84, Gln85, Val87, Leu92, Leu94, Tyr97, Met105, Cys136, Asn140, Ile146 and Met149 in inhibitor binding. The study provides a possible lead candidate and key amino acids involved in inhibitor recognition and binding at the active site of BRD4-BD1 protein. The findings might be of significance to medicinal chemists involved in the development of potent BRD4-BD1 inhibitors.

Impact of environmental temperature on the survival outcomes of breast cancer: A SEER-based study.

BACKGROUND: Experimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate and an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates will have better survival outcomes than patients living in colder climates. METHODS: A retrospective population-based analysis was conducted on 270,496 stage I-III breast cancer patients, who were retrieved from the Surveillance, Epidemiology and End Results (SEER) over the period from 1996 to 2017. The average annual temperature (AAT) was calculated based on city level data from the National Centers for Environmental Information. RESULTS: A total of 270, 496 patients were analyzed. Temperature as assessed in quartiles. After adjusting for potential confounders, patients who lived in the 3rd and 4th quartile temperature regions with AAT 56.7-62.5°F (3rd quartile) and > 62.5°F (4th quartile) had a 7% increase in the OS compared to patients living at AAT < 48.5°F (1st quartile) (HR 0.93, 95% CI 0.90-0.95 and HR 0.93, 95% CI 0.91-0.96, respectively). For DSS, When comparing AAT quartiles, patients living with AAT in the range of 56.7-62.5°F and > 62.5°F demonstrated a 7% increase each in DSS after adjustment (HR 0.93, 95% CI 0.90-0.96 and HR 0.93, 95% CI 0.90-0.96). CONCLUSIONS: Higher environmental temperatures are associated with significantly better OS and DSS in breast cancer patients. Future research is warranted to confirm this observation using large datasets to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

Creation of Multi-Principal Element Alloy NiCoCr Nanostructures via Nanosecond Laser-Induced Dewetting.

The multi-principal element alloy nanoparticles (MPEA NPs), a new class of nanomaterials, present a highly rewarding opportunity to explore new or vastly different functional properties than the traditional mono/bi/multimetallic nanostructures due to their unique characteristics of atomic-level homogeneous mixing of constituent elements in the nanoconfinements. Here, the successful creation of NiCoCr nanoparticles, a well-known MPEA system is reported, using ultrafast nanosecond laser-induced dewetting of alloy thin films. Nanoparticle formation occurs by spontaneously breaking the energetically unstable thin films in a melt state under laser-induced hydrodynamic instability and subsequently accumulating in a droplet shape via surface energy minimization. While NiCoCr alloy shows a stark contrast in physical properties compared to individual metallic constituents, i.e., Ni, Co, and Cr, yet the transient nature of the laser-driven process facilitates a homogeneous distribution of the constituents (Ni, Co, and Cr) in the nanoparticles. Using high-resolution chemical analysis and scanning nanodiffraction, the environmental stability and grain arrangement in the nanoparticles are further investigated. Thermal transport simulations reveal that the ultrashort (≈100 ns) melt-state lifetime of NiCoCr during the dewetting event helps retain the constituent elements in a single-phase solid solution with homogenous distribution and opens the pathway to create the unique MPEA nanoparticles with laser-induced dewetting process.

Application Scopes of Miniaturized MXene-Functionalized Electrospun Nanofibers-Based Electrochemical Energy Devices.

Exploring combinatorial materials, as well as rational device configuration design, are assumed to be the key strategies for deploying versatile electrochemical devices. MXene sheets have revealed a high hydrophilic surface with proper mechanical and electrical characteristics, rendering them supreme additive candidates to integrate in electrospun electrochemical power tools. The synergetic effects of MXene 2D layers with the nanofibrous networks can boost actuator responsive ability, battery capacity retention, fuel cell stability, sensor sensitivity, and supercapacitor areal capacitance. Their superior mechanical features can be endowed to the electrospun layers through the embedding of the MXene additive. In this review, the preparation and inherent features of the MXene configurations are briefly evaluated. The fabrication and overall performance of the MXene-loaded nanofibers applicable in electrochemical actuators, batteries, fuel cells, sensors, and supercapacitors are comprehensively figured out. Eventually, an outlook on the future development of MXene-based electrospun composites is presented. A substantial focus has been devoted to date to engineering conjugated MXene and electrospun fibrous frames. The potential performance of the MXene-decorated nanofibers presents a bright future of nanoengineering toward technological growth. Meanwhile, a balance between the pros and cons of the synthesized MXene composite layers is worthwhile to consider in the future.

Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.

Hurler Syndrome Glycosaminoglycans Decrease in Cerebrospinal Fluid without Brain-Targeted Therapy.

Novel therapies for Hurler syndrome aim to cross the blood-brain barrier (BBB) to target neurodegeneration by degrading glycosaminoglycans (GAG). BBB penetration has been assumed with decreased cerebrospinal fluid (CSF) GAG, yet little is known about CSF GAG without brain-targeting therapies. We compared pre-transplant CSF GAG in patients who were treatment naïve (n = 19) versus receiving standard non-BBB penetrating enzyme replacement therapy (ERT, n = 12). In the ERT versus treatment naïve groups, CSF GAG was significantly lower across all content assayed, raising questions about using CSF GAG decrements to show BBB penetration. Future studies should compare GAG reduction in standard versus novel therapies. ANN NEUROL 2023;94:1182-1186.

Biosynthesis of silver nanoparticle from flower extract of Dillenia indica and its efficacy as antibacterial and antioxidant.

Dillenia indica is a medicinal tree of the Dilleniaceae and its flower extract was used for the synthesis of silver nanoparticle (AgNPs). The optimal conditions for AgNPs synthesis were as such: 2 mM AgNO3, pH 4.5 and 48-h reaction time. The characteristic band of AgNPs was observed at the wavelength of 435 nm by UV-visible spectroscopic study. Fourier-transform infrared (FTIR) analysis depicted the involvement of several functional groups of plant extracts in the synthesis of AgNPs. Nanoparticles were mostly spherical shaped and uniformly distributed, when observation was made by Transmission electron microscopy (TEM). Energy Dispersive X-Ray (EDX) showed absorption peak approximately at 3 keV thus confirmed the presence of silver metal in AgNP. X-ray diffraction (XRD) investigation and selected area electron diffraction (SAED) patterns showed the crystalline nature of the AgNPs. Dynamic light scattering (DLS) analysis exhibited average size of the nanoparticles as 50.17 nm with a polydispersity index (PDI) value of 0.298. The zeta potential of nanoparticles was observed as -24.9 mV. To assess antibacterial activity, both AgNPs alone or its combination with the antibiotic were tried against six pathogenic bacteria. The combination of AgNPs with antibiotic was maximum effective against Shigella boydii (16.07 ± 0.35) and Klebsiella pneumoniae (15.03 ± 0.20). AgNPs alone showed maximum inhibition for both Gram-positive bacteria: methicillin-resistant Staphylococcus aureus (19.97 ± 0.20 mm) and Enterococcus faecium (19.80 ± 0.15 mm). Maximum inhibition of Enterobactor cloacae and Pseudomonas aeruginosa was observed by antibiotic taken alone. Evaluation through 2,2-diphenyl-1-picrylhydrazyl (DPPH) and DNA nicking assays demonstrated the antioxidant capabilities of the nanoparticles.

International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the current state of hematopoietic stem and progenitor cell-based genomic therapies and the challenges faced.

Genetic manipulation of hematopoietic stem cells (HSCs) is being developed as a therapeutic strategy for several inherited disorders. This field is rapidly evolving with several novel tools and techniques being employed to achieve desired genetic changes. While commercial products are now available for sickle cell disease, transfusion-dependent ß-thalassemia, metachromatic leukodystrophy and adrenoleukodystrophy, several challenges remain in patient selection, HSC mobilization and collection, genetic manipulation of stem cells, conditioning, hematologic recovery and post-transplant complications, financial issues, equity of access and institutional and global preparedness. In this report, we explore the current state of development of these therapies and provide a comprehensive assessment of the challenges these therapies face as well as potential solutions.

Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.

BACKGROUND: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. We tested the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF. METHODS: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice. RESULTS: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling. CONCLUSIONS: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Unveiling perceptions regarding post mastectomy breast reconstruction: A questionnaire-based survey of patients from central India.

INTRODUCTION: Post mastectomy breast reconstruction uptake remains low in the developing countries. We examined patient perspectives about it in a cohort of Indian breast cancer patients. METHODS: This prospective study was conducted at a tertiary care center in central India. All post mastectomy patients for breast cancer were interviewed via a survey questionnaire to assess their perspective regarding post mastectomy breast reconstruction. RESULTS: None of the 192 patients underwent immediate or delayed reconstruction by the end of 24 months follow-up. Age, education level, occupation and marital status did not affect the uptake of post mastectomy breast reconstruction. The most common patient-reported reasons for not having reconstruction were the desire to avoid additional surgery and the belief that it was not important (80% for each). System related factors such as additional cost of surgery and additional length of stay were reported to be important by 55% and 65% patients respectively. CONCLUSION: Our survey of 192 post mastectomy breast cancer patients showed that none opted for post mastectomy reconstruction, suggesting significant barriers to it. Understanding and addressing these barriers are crucial to ensuring comprehensive care for these breast cancer patients.

All-Arthroscopic Supraspinatus and Infraspinatus Muscle Advancement Leads to High Healing Rate and Excellent Outcomes in Patients With Massive, Retracted Rotator Cuff Tears, Even in Patients With Pseudoparalysis.

PURPOSE: To evaluate the clinical and radiographic outcomes of an all-arthroscopic rotator cuff repair technique involving muscle advancement and double-layer lasso loop (DLLL) repair for massive, retracted posterosuperior cuff tears. METHODS: This was a retrospective case series of patients with massive, retracted posterosuperior cuff tears who underwent the all-arthroscopic muscle advancement technique from March 2017 to September 2021, with a minimum follow-up of 12 months. Key steps included suprascapular nerve release, advancement of the supraspinatus and infraspinatus muscles, and DLLL repair. Preoperative and postoperative visual analog scale score for pain, American Shoulder and Elbow Surgeons (ASES) shoulder score, Constant score, University of California, Los Angeles (UCLA) shoulder score, active range of motion, and strength were compared. Preoperative and postoperative structural radiologic characteristics were analyzed. RESULTS: We evaluated 43 shoulders in 38 patients with a mean follow-up period of 18.8 months (range, 12-55 months). Of the 43 shoulders, 4 showed repair failure (9.3% retear rate). Visual analog scale, ASES, Constant, and UCLA scores significantly improved (P < .001) in patients who showed healing on postoperative magnetic resonance imaging (n = 39). ASES, Constant, and UCLA scores were significantly better in the healed group, with 100% exceeding the minimal clinically important difference for the ASES score and UCLA score and 84.2%, for Constant score. A lower proportion of patients in the retear group achieved the minimal clinically important difference. Active range of motion in all planes significantly improved for patients who had healed repairs (P < .001). Relative abduction strength, supraspinatus strength, and infraspinatus strength were at least 90% of those on the contralateral side. The recovery rate of pseudoparalysis (7 patients) was 100%. CONCLUSIONS: All-arthroscopic muscle advancement, coupled with DLLL repair, leads to a high healing rate with excellent clinical outcomes and recovery of strength to at least 90%, even in patients with pseudoparalysis. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Does forearm referencing using a retroversion guide achieve the targeted retroversion of the humeral component in reverse shoulder arthroplasty?

BACKGROUND: Component positioning affects clinical outcomes of reverse shoulder arthroplasty, which necessitates an implantation technique that is reproducible, consistent, and reliable. This study aims to assess the accuracy and precision of positioning the humeral component in planned retroversion using a forearm referencing guide. METHODS: Computed tomography scans of 54 patients (27 males and 27 females) who underwent primary reverse shoulder arthroplasty for osteoarthritis or cuff tear arthropathy were evaluated. A standardized surgical technique was used to place the humeral stem in 15° of retroversion. Version was assessed intraoperatively visualizing the retroversion guide from above and referencing the forearm axis. Metal subtraction techniques from postoperative computed tomography images allowed for the generation of 3D models of the humerus and for evaluation of the humeral component position. Anatomical humeral plane and implant planes were defined and the retroversion 3D angle between identified planes was recorded for each patient. Accuracy and precision were assessed. A subgroup analysis evaluated differences between male and female patients. RESULTS: The humeral retroversion angle ranged from 0.9° to 22.8°. The majority (81%) of the measurements were less than 15°. Mean retroversion angle (±SD) was 9.9° ± 5.8° (95% CI 8.4°-11.5°) with a mean percent error with respect to 15° of -34% ± 38 (95% CI -23 to -44). In the male subgroup (n = 27, range 3.8°-22.5°), the mean retroversion angle was 11.9° ± 5.4° (95% CI 9.8°-14.1°) with a mean percent error with respect to 15° of -21% ± 36 (95% CI -6 to -35). In the female subgroup (n = 27, range 0.9°-22.8°), mean retroversion angle was 8.0° ± 5.5° (95% CI 5.8°-10.1°) and the mean percent error with respect to 15° was -47% ± 36 (95% CI -32 to -61). The differences between the 2 gender groups were statistically significant (P = .006). CONCLUSION: Referencing the forearm using an extramedullary forearm referencing system to position the humeral stem in a desired retroversion is neither accurate nor precise. There is a nonnegligible tendency to achieve a lower retroversion than planned, and the error is more marked in females.

Medial Scapular Body (MSB) Goutallier Classification - MRI based reliability and validity of evaluation of the Goutallier classification for grading fatty infiltration of the rotator cuff.

INTRODUCTION: The degree of atrophy and fatty infiltration of rotator cuff muscle belly is a key predictor for cuff repairability. Traditionally, Goutallier grading of fatty infiltration is assessed at sagittal scapular Y-view. Massive rotator cuff tears are associated with tendon retraction and medial retraction of cuff musculature, resulting in medialization of the muscle bulk. Thus, standard Y-view can misrepresent the region of interest and may misguide clinicians when assessing repairability. It is hypothesized that by assessing the muscle belly with multiple medial sagittal MRI sections at medial scapular body, the Medial Scapular Body - Goutallier Classification (MSB-GC) will improve reliability and repeatability giving a more representative approximation to the degree of fatty infiltration, as compared with original Y-view. METHODS: Fatty infiltration of the rotator cuff muscles were classified based on the Goutallier grade (0 to 4) at three defined sections section 1: original Y-view; section 2: level of suprascapular notch; section 3: three cm medial to suprascapular notch on MRI scans. Six sub-specialist fellowship trained shoulder surgeons, and three musculoskeletal radiologists independently evaluated deidentified MRI scans of included patients. RESULTS: Out of 80 scans, 78% (n=62) were massive cuff tears involving supraspinatus, infraspinatus and subscapularis tendon. Inter-observer reliability (consistency between observers) for Goutallier grade was excellent for all three predefined sections (range:0.87-0.95). Intra-observer reliability (repeatability) for Goutallier grade was excellent for all three sections and four rotator cuff muscles (range:0.83-0.97). There was a moderate to strong positive correlation of Goutallier grades between sections 1 and 3 and between sections 2 and 3 and these were statistically significant (p<0.001). There was a reduction in the severity of fatty infiltration on the Goutallier classification from sections 1 to 3 across all muscles. 42.5% of both supraspinatus and infraspinatus were downgraded by one, 20% of supraspinatus and 3.8% of infraspinatus were downgraded by 2 and 2.5% of supraspinatus were downgraded by 3. CONCLUSION: This study found that applying the Goutallier classification to more medial MRI sections (MSB-GC) resulted in assignment of lower grades for all rotator cuff muscles. Additionally, this method demonstrated excellent test-retest reliability and repeatability. Inclusion of a more medial view or whole scapula on MRI, especially in advanced levels of tear retraction, could be more reliable and representative for assessment of the degree of fatty infiltration within the muscle bulk that could help predict tear repairability and therefore improve clinical decision-making which should be studied further in clinical studies.

Comparison of Shoulder Range of Motion Quantified with Mobile Phone Video-Based Skeletal Tracking and 3D Motion Capture-Preliminary Study.

BACKGROUND: The accuracy of human pose tracking using smartphone camera (2D-pose) to quantify shoulder range of motion (RoM) is not determined. METHODS: Twenty healthy individuals were recruited and performed shoulder abduction, adduction, flexion, or extension, captured simultaneously using a smartphone-based human pose estimation algorithm (Apple's vision framework) and using a skin marker-based 3D motion capture system. Validity was assessed by comparing the 2D-pose outcomes against a well-established 3D motion capture protocol. In addition, the impact of iPhone positioning was investigated using three smartphones in multiple vertical and horizontal positions. The relationship and validity were analysed using linear mixed models and Bland-Altman analysis. RESULTS: We found that 2D-pose-based shoulder RoM was consistent with 3D motion capture (linear mixed model: R2 > 0.93) but was somewhat overestimated by the smartphone. Differences were dependent on shoulder movement type and RoM amplitude, with adduction the worst performer among all tested movements. All motion types were described using linear equations. Correction methods are provided to correct potential out-of-plane shoulder movements. CONCLUSIONS: Shoulder RoM estimated using a smartphone camera is consistent with 3D motion-capture-derived RoM; however, differences between the systems were observed and are likely explained by differences in thoracic frame definitions.

Effect of Laparoscopic Cholecystectomy on 25- Hydroxyvitamin D Levels and Bone Mineral Density in Post Menopausal Women.

Background Laparoscopic cholecystectomy (LC) is the gold standard management for benign gallbladder diseases. It has been observed that there is alteration in vitamin D levels and bone mineral density after cholecystectomy due to altered enterohepatic circulation.With increase in average age expectancy of the population, low levels of vitamin D levels and osteoporosis after cholecystectomies might cause increased health care burden.Methods A prospective observational study was planned between 1st Jan 2022 to 30th Jun 2023 in the Department of General Surgery at PGIMER Chandigarh, a tertiary care hospital in north India. One hundred and three post-menopausal women who underwent LC and met the inclusion and exclusion criteria were included in the study. All participants underwent estimation of vitamin D and bone mineral density preoperatively and 3rdpost operative month (POM).Results The mean age of the patients was58.46 ± 7.44. Pain abdomen was present in 68(66%) patients, 18 had epigastric discomfort and 17 had dyspepsia. The mean levels of vit D decreased from21.92 at the baseline to 20.12 at 3rd POM(P < 0.001). There was significant change in t score Femoral Neck (-1.12 vs -1.15, P < 0.001) andLumbar spine L1-L4 -1.98 vs-1.98 (P = 0.033). z-Scores of the Femoral Neck were -0.34 vs -0.54 (p < 0.001) and of Lumbar spine L1-L4 were -0.95 vs 1.02 (P < 0.001). The decrease in fracture risk for the femoral neck(p= 0.344) and the lumbar spine (P = 0.223) were not statistically significant.Conclusion There is significant decrease in vitamin D and BMD level after LC in post-menopausal females.

TIP60 acts as a regulator of genes involved in filopodia formation and cell migration during wound healing.

Wound healing is a complex phenomenon that requires coordination of numerous molecular and cellular changes to facilitate timely and efficient repair of the damaged tissue. Although many of these molecular pathways have been detailed, others remain to be elucidated. In the present work, we show for the first time, roles for the acetyltransferase TIP60 and nuclear receptor transcription factor PXR in this process, participating in wound healing by altering actin dynamics and cellular motility. We found that in response to wound-injury, TIP60 induces rapid formation of filopodia at the wounded cell front, leading to enhanced cell migration and faster closure of the wound. Further, qPCR analysis revealed heightened expression of Cdc42 and ROCK1 genes, key regulators involved in filopodia formation and actin reorganization, exclusively in TIP60-PXR-expressing cells upon wound-induction. We also performed ChIP assays to confirm the context-specific binding of TIP60 on the ROCK1 promoter and demonstrated that the TIP60 chromodomain is essential for loading of the TIP60-PXR complex onto the chromatin. Results from immunoprecipitation assays revealed that during the wounded condition, TIP60 alters the chromatin microenvironment by specifically acetylating histones H2B and H4, thereby modulating the expression of target genes. Overall, findings of this study show that TIP60 is a novel regulator of the wound healing process by regulating the expression of wound repair-related genes.

Evaluation of prostate cancer tissue metabolomics: would clinics utilise it for diagnosis?

The difficulty of diagnosing prostate cancer (PC) with the available biomarkers frequently leads to over-diagnosis and overtreatment of PC, underscoring the need for novel molecular signatures. The purpose of this review is to provide a summary of the currently available cellular metabolomics for PC molecular signatures. A comprehensive search on PubMed was conducted to find studies published between January 2004 and August 2022 that reported biomarkers for PC detection, development, aggressiveness, recurrence and treatment response. Although potential studies have reported the presence of distinguishing molecules that can distinguish between benign and cancerous prostate tissue. However, there are few studies looking into signature molecules linked to disease development, therapy response or tumour recurrence. The majority of these studies use high-dimensional datasets, and the number of potential metabolites investigated frequently exceeds the size of the available samples. In light of this, pre-analytical, statistical, methodological and confounding factors such as antiandrogen therapy (NAT) may also be linked to the identified chemometric multivariate differences between PC and relevant control samples in the datasets. Despite the methodological and procedural challenges, a range of methodological groups and processes have consistently identified a number of signature metabolites and pathways that appear to imply a substantial involvement in the cellular metabolomics of PC for tumour formation and recurrence.

Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function.

BACKGROUND: Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT. METHODS: Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation. RESULTS: Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF. CONCLUSION: Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT.

Cardiac 31P MR spectroscopy: development of the past five decades and future vision-will it be of diagnostic use in clinics?

In the past five decades, the use of the magnetic resonance (MR) technique for cardiovascular diseases has engendered much attention and raised the opportunity that the technique could be useful for clinical applications. MR has two arrows in its quiver: One is magnetic resonance imaging (MRI), and the other is magnetic resonance spectroscopy (MRS). Non-invasively, highly advanced MRI provides unique and profound information about the anatomical changes of the heart. Excellently developed MRS provides irreplaceable and insightful evidence of the real-time biochemistry of cardiac metabolism of underpinning diseases. Compared to MRI, which has already been successfully applied in routine clinical practice, MRS still has a long way to travel to be incorporated into routine diagnostics. Considering the exceptional potential of 31P MRS to measure the real-time metabolic changes of energetic molecules qualitatively and quantitatively, how far its powerful technique should be waited before a successful transition from "bench-to-bedside" is enticing. The present review highlights the seminal studies on the chronological development of cardiac 31P MRS in the past five decades and the future vision and challenges to incorporating it for routine diagnostics of cardiovascular disease.

Characterization of primary hyperparathyroidism based on target organ involvement: An analysis from the Indian PHPT registry.

BACKGROUND: It has been a matter of debate for long time about the existence of two distinct phenotypes of primary hyperparathyroidism (PHPT) predisposed to either renal or skeletal manifestation. OBJECTIVE: To differentiate characteristics of symptomatic PHPT patients based on the presence of skeletal or renal involvement. DESIGN: Retrospective analysis of data from the Indian PHPT registry. PATIENTS: PHPT patients were divided into four discrete groups: asymptomatic, presenting with renal manifestations alone, skeletal manifestations alone, and both skeletal and renal manifestations. MEASUREMENTS: Clinical, biochemical, and tumour weight and histopathological characteristics of these groups were compared. RESULTS: Of the 229 eligible patients, 45 were asymptomatic, 62 had renal manifestations, 55 had skeletal manifestations, and 67 had both skeletal and renal manifestations. Patients with both skeletal and renal manifestations had higher serum calcium levels than those with isolated skeletal involvement [12.5 (11.1-13.7) mg/dL, 11.2 (10.6-12.3) mg/dL, respectively; p < .05]. Serum alkaline phosphatase (AP), plasma parathyroid hormone (PTH) levels, and parathyroid tumour weight were significantly higher in patients with isolated skeletal, and both skeletal and renal manifestations, compared to the other two groups. A preoperative PTH and AP level of 300 pg/mL and 152 U/L, predicted the risk of developing skeletal involvement with sensitivity and specificity of 71%, 70%, and 69%, 67%, respectively. CONCLUSIONS: We observed distinct skeletal and renal phenotypic subgroups among PHPT patients with characteristic biochemical and hormonal patterns with higher parathyroid disease burden in patients with skeletal complications compared to those with isolated renal manifestation.