Antibiotic-associated neutropenia is marked by depletion of intestinal Lachnospiraceae in pediatric patients.

Hematologic side effects are associated with prolonged antibiotic exposure in up to 34% of patients. Neutropenia, reported in 10-15% of patients, increases the risk of sepsis and death. Murine studies have established a link between the intestinal microbiota and normal hematopoiesis. We sought to identify predisposing factors, presence of microbiota-derived metabolites, and changes in intestinal microbiota composition in otherwise healthy pediatric patients who developed neutropenia after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics and at the time of neutropenia. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and type of infection or type of antibiotic used; however intensive care unit admission and length of therapy were associated with neutropenia. Reduced intestinal microbiome richness and decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism and fatty acid metabolism that are known to be produced by Lachnospiraceae . Our study confirms a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis. As the microbiome is a key determinant of stem cell transplant and immunotherapy outcomes, these findings are likely to be of broad significance. Key Points: Neutropenia occurred in 17% of patients receiving prolonged antibiotic therapy.We found no association between neutropenia and type of infection or class of antibiotic used. Development of neutropenia after prolonged antibiotic treatment was associated with decreased prevalence of Lachnospiraceae and Lachnospiraceae metabolites such as citrulline.

Osteomyelitis and non-coding RNAS: A new dimension in disease understanding.

Osteomyelitis, a debilitating bone infection, presents considerable clinical challenges due to its intricate etiology and limited treatment options. Despite strides in surgical and chemotherapeutic interventions, the treatment landscape for osteomyelitis remains unsatisfactory. Recent attention has focused on the role of non-coding RNAs (ncRNAs) in the pathogenesis and progression of osteomyelitis. This review consolidates current knowledge on the involvement of distinct classes of ncRNAs, including microRNAs, long ncRNAs, and circular RNAs, in the context of osteomyelitis. Emerging evidence from various studies underscores the potential of ncRNAs in orchestrating gene expression and influencing the differentiation of osteoblasts and osteoclasts, pivotal processes in bone formation. The review initiates by elucidating the regulatory functions of ncRNAs in fundamental cellular processes such as inflammation, immune response, and bone remodeling, pivotal in osteomyelitis pathology. It delves into the intricate network of interactions between ncRNAs and their target genes, illuminating how dysregulation contributes to the establishment and persistence of osteomyelitic infections. Understanding their regulatory roles may pave the way for targeted diagnostic tools and innovative therapeutic interventions, promising a paradigm shift in the clinical approach to this challenging condition. Additionally, we delve into the promising therapeutic applications of these molecules, envisioning novel diagnostic and treatment approaches to enhance the management of this challenging bone infection.

Multiple roles for basement membrane proteins in cancer progression and EMT.

Metastasis or the progression of malignancy poses a major challenge in cancer therapy and is the principal reason for increased mortality. The epithelial-mesenchymal transition (EMT) of the basement membrane (BM) allows cells of epithelial phenotype to transform into a mesenchymal-like (quasi-mesenchymal) phenotype and metastasize via the lymphovascular system through a metastatic cascade by intravasation and extravasation. This helps in the progression of carcinoma from the primary site to distant organs. Collagen, laminin, and integrin are the prime components of BM and help in tumor cell metastasis, which makes them ideal cancer drug targets. Further, recent studies have shown that collagen, laminin, and integrin can be used as a biomarker for metastatic cells. In this review, we have summarized the current knowledge of such therapeutics, which are either currently in preclinical or clinical stages and could be promising cancer therapeutics. DATA AVAILABILITY: Not applicable.

Unravelling the multi-faceted regulatory role of polyamines in plant biotechnology, transgenics and secondary metabolomics.

Polyamines (PAs) are ubiquitous low-molecular-weight, aliphatic compounds with wide as well as complex application in fundamental areas of plant growth and development. PAs are mediator of basic metabolism of organisms which include cell division and differentiation, biotic and abiotic stress tolerance, reversal of oxidative damage, stabilization of nucleic acids, and protein and phospholipid binding. In plants, it attributes in direct and indirect organogenesis, endogenous phytohormone regulation, cellular compartmentalization, fruit and flower development, senescence, and secondary metabolite production which are highly tuned as first line of defense response. There are several aspects of polyamine-directed mechanism that regulate overall plant growth in vitro and in vivo. In the present review, we have critically discussed the role played by polyamine on the enhanced production of bioactive natural products and how the same polyamines are functioning against different environmental stress conditions, i.e., salinity, drought, high CO2 content, herbivory, and physical wounding. The role of polyamines on elicitation process has been highlighted previously, but it is important to note that its activity as growth regulator under in vitro condition is correlated with an array of intertwined mechanism and physiological tuning. Medicinal plants under different developmental stages of micropropagation are characterized with different functional aspects and regulatory changes during embryogenesis and organogenesis. The effect of precursor molecules as well as additives and biosynthetic inhibitors of polyamines in rhizogenesis, callogenesis, tuberization, embryogenesis, callus formation, and metabolite production has been discussed thoroughly. The beneficial effect of exogenous application of PAs in elicitation of secondary metabolite production, plant growth and morphogenesis and overall stress tolerance are summarized in this present work. KEY POINTS: • Polyamines (PAs) play crucial roles in in vitro organogenesis. • PAs elicitate bioactive secondary metabolites (SMs). • Transgenic studies elucidate and optimize PA biosynthetic genes coding SMs.

Anatomical grades of nerve sparing: a risk-stratified approach to neural-hammock sparing during robot-assisted radical prostatectomy (RARP).

OBJECTIVES: • To report the potency and oncological outcomes of patients undergoing robot-assisted radical prostatectomy (RARP) using a risk-stratified approach based on layers of periprostatic fascial dissection. • We also describe the surgical technique of complete hammock preservation or nerve sparing grade 1. PATIENTS AND METHODS: • This is a retrospective study of 2317 patients who had robotic prostatectomy by a single surgeon at a single institution between January 2005 and June 2010. • Included patients were those with ≥ 1 year of follow-up and who were potent preoperatively, defined as having a sexual health inventory for men (SHIM) questionnaire score of >21; thus, the final number of patients in the study cohort was 1263. • Patients were categorized pre-operatively by a risk-stratified approach into risk grades 1-4, where risk grade 1 patients received nerve-sparing grade 1 or complete hammock preservation and so on for risk grades 2-4, as long as intraoperative findings permitted the planned nerve sparing. • We considered return to sexual function post-operatively by two criteria: i) ability to have successful intercourse (score of ≥ 4 on question 2 of the SHIM) and ii) SHIM >21 or return to baseline sexual function. RESULTS: • There was a significant difference across different NS grades in terms of the percentages of patients who had intercourse and returned to baseline sexual function (P < 0.001), with those that underwent NS grade 1 having the highest rates (90.9% and 81.7%) as compared to NS grades 2 (81.4% and 74.3%), 3 (73.5% and 66.1%), and 4 (62% and 54.5%). • The overall positive surgical margin (PSM) rates for patients with NS grades 1, 2, 3, and 4 were 9.9%, 8.1%, 7.2%, and 8.7%, respectively (P = 0.636). • The extraprostatic extension rates were 11.6%, 14.3%, 29.3%, and 36.2%, respectively (P < 0.001). • Similarly, in patients younger than 60, intercourse and return to baseline sexual function rates were 94.9% and 84.3% for NS grade 1 as compared to 85.5% and 77.2% for NS grades 2, 76.9% and 69% for NS grades 3, and 64.8% and 57.7% for NS Grade 4 (P < 0.001). CONCLUSIONS: • The risk-stratified approach and anatomical technique of neural-hammock sparing described in the present manuscript was effective in improving potency outcomes of patients without compromising cancer control. • Patients with greater degrees of NS had higher rates of intercourse and return to baseline sexual function without an increase in PSM rates.