Impact of Early Nutrition Interventions on the Growth and Development of Preterm Infants: A Narrative Review.

Preterm birth remains a significant global health concern as it can lead to various health complications and long-term developmental challenges. Early nutrition intervention plays a crucial role in optimizing the growth, development, and overall health outcomes of premature infants. This review aims to summarize and analyze the existing literature regarding the effect of early nutrition interventions on premature babies. A comprehensive search was conducted through various electronic databases, including PubMed, Scopus, and Google Scholar, focusing on nutrition interventions specifically targeting premature infants. The review highlights the benefits of early nutrition interventions, including enteral and parenteral feeding, human milk, and the provision of specific nutrients. These interventions have been shown to enhance growth rates, promote neurodevelopmental outcomes, reduce the incidence and severity of retinopathy of prematurity (ROP), reduce the risk of infection, and improve overall morbidity and mortality rates in premature babies. Overall, the findings from this review suggest that early nutrition interventions have a positive impact on the health and developmental outcomes of premature babies. However, further research is required to determine the optimal approaches, optimal timing, and long-term effects of various interventions. Collaboration between healthcare providers, researchers, and families is crucial in implementing evidence-based nutrition practices and supporting the growth and development of premature infants.

CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of nontransformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional readthrough in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure, and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.

Retraction: Hemichorea: A Rare Neurological Complication of Diabetes Mellitus.

[This retracts the article DOI: 10.7759/cureus.21131.].

Addressing Occupational Back Pain: A Systematic Review of Preventive and Therapeutic Strategies.

Occupational back pain has emerged as a significant public health concern. Despite several efforts to mitigate the adverse effects of occupational back pain, this issue still persists across the globe. This systematic review summarizes the preventive and therapeutic options available for managing occupational back pain. A systemic search was carried out in various databases including PubMed, Web of Science, CINAHL Ultimate, and Scopus to identify relevant literature. The search was also extended to Google Scholar to identify more relevant studies. A combination of keywords was used during the search. Studies were included if they focused on occupational back pain, investigated preventive and treatment options, and were published in English. A total of 20 relevant studies, including 62,176 participants, were included in this systemic review. Out of these 20 studies, 10 were randomized control trials, four were cross-sectional studies, two were longitudinal studies, one was a single-blinded clinical study, two were prospective studies, and the remaining one was a pilot study. This systemic review identified various interventions to improve occupational back pain. The common therapeutic strategies included educational programs, physio and rehab interventions, acupuncture, mixed treatment strategies, reflexology, massage, yoga, active physical therapy, and real-time occupational internet-based interventions. Some studies also reported the effectiveness of opioid therapy and non-steroidal anti-inflammatory drugs for managing back pain. Findings indicated that these therapies effectively reduced occupational back pain and improved quality of life. However, opioid therapy uses also raised safety concerns. The findings of this systemic review highlight the importance of adopting evidence-based strategies to address occupational back pain effectively.

Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer.

PURPOSE: This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling. EXPERIMENTAL DESIGN: Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling. RESULTS: LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs. CONCLUSIONS: We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.

Succinate dehydrogenase inversely regulates red cell distribution width and healthy life span in chronically hypoxic mice.

Increased red cell distribution width (RDW), which measures erythrocyte mean corpuscular volume (MCV) variability (anisocytosis), has been linked to early mortality in many diseases and in older adults through unknown mechanisms. Hypoxic stress has been proposed as a potential mechanism. However, experimental models to investigate the link between increased RDW and reduced survival are lacking. Here, we show that lifelong hypobaric hypoxia (~10% O2) increased erythrocyte numbers, hemoglobin, and RDW, while reducing longevity in male mice. Compound heterozygous knockout (hKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc, and Sdhd reduced Sdh subunit protein levels, reduced RDW, and increased healthy life span compared with WT mice in chronic hypoxia. RDW-SD, a direct measure of MCV variability, and the SD of MCV showed the most statistically significant reductions in Sdh hKO mice. Tissue metabolomic profiling of 147 common metabolites showed the largest increase in succinate with elevated succinate/fumarate and succinate/oxoglutarate (2-ketoglutarate) ratios in Sdh hKO mice. These results demonstrate that mitochondrial complex II level is an underlying determinant of both RDW and healthy life span in hypoxia and suggest that therapeutic targeting of Sdh might reduce high RDW-associated clinical mortality in hypoxic diseases.

The Effect of Sealer Application Methods on Voids Volume after Aging of Three Calcium Silicate-Based Sealers: A Micro-Computed Tomography Study.

During obturation, air voids are undesirable as they may provide shelter for microorganisms or passage for fluids. This study aimed to compare the occurrence of voids between three calcium silicate-based sealers (CSBSs) (MTA-Fillapex, BioRoot-RCS, Bio-C) and the change in their volume after aging. In addition, we aimed to compare voids when using two sealer application methods: lentulo-spiral (LS) and gutta-percha (GP) cone. Thirty extracted mandibular premolars (n = 30) were endodontically prepared and obturated using single GP cone (SGPC) technique. Each sealer was applied to 10 teeth (n = 10) using LS or GP. Micro-computed tomography (micro-CT) was used to quantify the volume of root filling and voids before and after 8-week storage in a phosphate-rich medium. The percentage of root filling and voids were compared between the groups using a Mann-Whitney U test and Kruskal-Wallis test with a Bonferroni correction. Before aging, the percentages of root filling volume after obturation were comparable with no significant differences between sealers (p = 0.325) or application methods (p = 0.950). After aging, the voids' volume increased significantly in all sealers (p ≤ 0.05). However, no significant differences were found between sealers (p = 0.302). In conclusion, voids in CSBSs may not reduce in size with aging; hence, SGPC should be carefully selected for suitable cases.

Hemichorea: A Rare Neurological Complication of Diabetes Mellitus.

Diabetes mellitus is a prevalent metabolic disorder that has a wide range of complications. Neurological complications are common and include stroke and peripheral neuropathy. However, hemichorea is a very rare manifestation of diabetes mellitus. Chorea can be due to primary inherited conditions or secondary to other disorders. Careful evaluation of patients with chorea is crucial since secondary chorea can be managed with the treatment of the underlying cause. We report the case of a 51-year-old man who presented to the emergency department with a two-week history of sudden involuntary and random-appearing movements of the right upper and lower extremities. These movements were non-suppressible and disappeared during sleep. Further, the movements were not associated with any neurological symptoms, including headache, dizziness, weakness, sensory deficits, or loss of consciousness. The patient had a longstanding history of hypertension and diabetes mellitus. He reported that he was not compliant with his medications. Laboratory investigation revealed a very high level of blood glucose (580 mg/dL) with associated pseudohyponatreamia (127 mEq/L). Head computed tomography scan showed increased density in right caudate nuclei and putamen with no surrounding edema or mass effect. The findings were suggestive of non-ketotic hyperglycemic hemichorea based on the clinical, laboratory, and radiological laboratory findings. The patient received insulin therapy according to sliding-scale protocol. The chorea movements gradually improved and completely disappeared after the fourth day of admission with the normalization of glucose level. In view of this, emergency medicine physicians should consider non-ketotic hyperglycemia as a potential underlying etiology of acute hemichorea.

Drivers of Gene Expression Dysregulation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a poor prognosis. The functional consequences of common genetic aberrations and their roles in treatment strategies have been extensively reviewed. In addition to these genomic aberrations, consideration of non-genetic drivers of altered oncogene expression is essential to account for the diversity in PDAC phenotypes. In this review we seek to assess our current understanding of mechanisms of gene expression dysregulation. We focus on four drivers of gene expression dysregulation, including mutations, transcription factors, epigenetic regulators, and RNA stability/isoform regulation, in the context of PDAC pathogenesis. Recent studies provide much-needed insight into the role of gene expression dysregulation in dissecting tumor heterogeneity and stratifying patients for the development of personalized treatment strategies.

RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization.

Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1ß and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma.

Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3'-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here, we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDACs). We report widespread, recurrent, and functionally relevant 3'-UTR alterations associated with gene expression changes of known and newly identified PDAC growth-promoting genes and experimentally validate the effects of these APA events on protein expression. We find enrichment for APA events in genes associated with known PDAC pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3'-UTR forms of metabolic genes. Survival analyses reveal a subset of 3'-UTR alterations that independently characterize a poor prognostic cohort among PDAC patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDAC. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDAC cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDAC via the loss of miRNA regulation.

Effect of Energy Input on Microstructure and Mechanical Properties of Titanium Aluminide Alloy Fabricated by the Additive Manufacturing Process of Electron Beam Melting.

Titanium aluminides qualify adequately for advanced aero-engine applications in place of conventional nickel based superalloys. The combination of high temperature properties and lower density gives an edge to the titanium aluminide alloys. Nevertheless, challenges remain on how to process these essentially intermetallic alloys in to an actual product. Electron Beam Melting (EBM), an Additive Manufacturing Method, can build complex shaped solid parts from a given feedstock powder, thus overcoming the shortcomings of the conventional processing techniques such as machining and forging. The amount of energy supplied by the electron beam has considerable influence on the final build quality in the EBM process. Energy input is decided by the beam voltage, beam scan speed, beam current, and track offset distance. In the current work, beam current and track offset were varied to reflect three levels of energy input. Microstructural and mechanical properties were evaluated for these samples. The microstructure gradually coarsened from top to bottom along the build direction. Whereas higher energy favored lath microstructure, lower energy tended toward equiaxed grains. Computed tomography analysis revealed a greater amount of porosity in low energy samples. In addition, the lack of bonding defects led to premature failure in the tension test of low energy samples. Increase in energy to a medium level largely cancelled out the porosity, thereby increasing the strength. However, this trend did not continue with the high energy samples. Electron microscopy and X-ray diffraction investigations were carried out to understand this non-linear behavior of the strength in the three samples. Overall, the results of this work suggest that the input energy should be considered primarily whenever any new alloy system has to be processed through the EBM route.