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Harris lines (HLs) are radiographically visible transverse lines of thickened bone that develop from temporary growth cessation during early life. Often attributed to physiological stress during development, HLs are frequently observed in the long bones of adolescents and become less visible over time due to bone remodeling. In recent years, the validity of HL as a sign of stress has been called into question and the methods used in studying HL through X‐ray analysis scrutinized. In this study, 80 individuals from the Middle Holocene Cis‐Baikal region of Siberia, from the Early Neolithic (EN; 7560–6660 HPD cal. BP) and Late Neolithic (LN; 6060–4970 HPD cal. BP), were studied for the presence and severity of HL. Radiographic analysis employed both the traditional clinical anteroposterior (A–P) orientation and a potentially improved mediolateral (M–L) orientation. EN groups in the Cis‐Baikal are known to have experienced higher levels than their LN counterparts; thus, if HL reflect stress experiences, we expected to see more HL in the EN population compared with the LN population. We also expected more visible HL in the M–L orientation due to the suggested improvement in capturing more lines compared with the A–P orientation. While the results support the use of M–L orientation during X‐ray capture of HL, there was not a higher number of HL in the EN population as expected. Instead, no significant differences were found in HL severity between the EN and LN populations, and age‐at‐death resulted in a greater effect on HL counts regardless of mortuary site. The results from this study align not with known stress data from the Middle Holocene Cis‐Baikal populations but rather with data pertaining to known growth patterns. We therefore advocate against the use of HL as a sign of physiological stress and instead suggest HL as a reflection of bone growth trajectory. [ABSTRACT FROM AUTHOR]

Abstract Mesotrypsin, encoded by the PRSS3 gene, is a distinctive trypsin isoform renowned for its exceptional resistance to traditional trypsin inhibitors and unique substrate specificity. Within the skin epidermis, this protein primarily expresses in the upper layers of the stratified epidermis and plays a crucial role in processing pro-filaggrin (Pro-FLG). Although prior studies have partially elucidated its functions using primary cultured keratinocytes, challenges persist due to these cells' differentiation-activated cell death program. In the present study, HaCaT keratinocytes, characterized by minimal endogenous mesotrypsin expression and sustained proliferation in differentiated states, were utilized to further scrutinize the function of mesotrypsin. Despite the ready degradation of the intact form of active mesotrypsin in these cells, fusion with Venus, flanked by a peptide linker, enables evasion from the protein elimination machinery, thus facilitating activation of the Pro-FLG processing system. Inducing Venus-mesotrypsin expression in the cells resulted in a flattened phenotype and reduced proliferative capacity. Moreover, these cells displayed altered F-actin assembly, enhanced E-cadherin adhesive activity, and facilitated tight junction formation without overtly influencing epidermal differentiation. These findings underscore mesotrypsin's potentially pivotal role in shaping the characteristic cellular morphology of upper epidermal layers.

Abstract Background Atrophic autoimmune thyroiditis (AAT) is a rare phenotype of autoimmune thyroiditis (AT) in pediatric age. AAT occurs without thyroid enlargement leading to a delay in its diagnosis. Growth impairment is infrequent in autoimmune thyroiditis, if timely diagnosed. Prolonged severe hypothyroidism is a rare cause of pituitary hyperplasia (PH) in childhood. Loss of thyroxine negative feedback causes a TRH-dependent hyperplasia of pituitary thyrotroph cells resulting in adenohypophysis enlargement. A transdifferentiation of pituitary somatotroph cells into thyrotroph cells could explain growth failure in those patients. Methods Twelve patients were retrospectively evaluated at five Italian and Polish Centres of Pediatric Endocrinology for height growth impairment. In all Centres, patients underwent routine clinical, biochemical and radiological evaluations. Results At the time of first assessment, the 75% of patients presented height growth arrest, while the remaining ones showed growth impairment. The study of thyroid function documented a condition of hypothyroidism, due to AT, in the entire cohort, although all patients had no thyroid enlargement. Thyroid ultrasound showed frankly atrophic or normal gland without goiter. Cerebral MRI documented symmetrical enlargement of the adenohypophysis in all patients and a homogeneous enhancement of the gland after the administration of Gadolinium-DPTA. Replacement therapy with levothyroxine was started and patients underwent close follow-up every 3 months. During the 12 months of follow-up, an improvement in terms of height growth has been observed in 88% of patients who continued the follow-up. Laboratory findings showed normalization of thyroid function and the control brain MRI documented complete regression of PH to a volume within the normal range for age and sex. Conclusions This is the largest pediatric cohort with severe autoimmune primary hypothyroidism without goiter, but with pituitary hyperplasia in which significant growth impairment was the most evident presenting sign. AAT phenotype might be correlated with this specific clinical presentation. In youths with growth impairment, hypothyroidism should always be excluded even in the absence of clear clinical signs of dysthyroidism.

The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β‐catenin pathway, with significant downregulation of both Ser 675‐phosphorylated β‐catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle‐related gene expression, and also induced growth arrest in SW480 and HCT‐116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C‐δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114‐induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β‐catenin. Consequently, formation of a T‐cell factor‐4 (TCF4)/β‐catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle‐related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment.

Background: Fractures through the physis account for 18–30% of all paediatric fractures, leading to growth arrest in up to 5.5% of cases. We have limited knowledge to predict which physeal fractures result in growth arrest and subsequent deformity or limb length discrepancy. The purpose of this study is to identify factors associated with physeal growth arrest to improve patient outcomes. Methods: This prospective cohort study was designed to develop a clinical prediction model for growth arrest after physeal injury. Patients ≤ 18 years old presenting within four weeks of injury were enrolled if they had open physes and sustained a physeal fracture of the humerus, radius, ulna, femur, tibia or fibula. Patients with prior history of same-site fracture or a condition known to alter bone growth or healing were excluded. Demographic data, potential prognostic indicators, and radiographic data were collected at baseline, during healing, and at one- and two-years post-injury. Results: A total of 332 patients had at least six months of follow-up or a diagnosis of growth arrest within six months of injury. In a comparison analysis, patients who developed growth arrest were more likely to be older (12.8 years vs. 9.4 years) and injured on the right side (53.0% vs. 45.7%). Initial displacement and angulation rates were higher in the growth arrest group (59.0% vs. 47.8% and 47.0% vs. 38.8%, respectively), but the amount of angulation was similar (27.0° vs. 28.4°). Rates of growth arrest were highest in distal femoral fractures (86%). Conclusions: The incidence of growth arrest in this patient population appears higher than the past literature reports at 30.1%. However, there may be variances in diagnostic criteria for growth arrest, and the true incidence may be lower. A number of patients were approaching skeletal maturity, and any growth arrest is likely to have less clinical significance in these cases. Further prospective long-term follow-up is required to determine risk factors, incidence, and true clinical impact of growth arrest when it does occur. [ABSTRACT FROM AUTHOR]

The peptide mimetic, NC114, is a promising anticancer compound that specifically kills colorectal cancer cells without affecting normal colon epithelial cells. In our previous study, we observed that NC114 inhibited the Wnt/β‐catenin pathway, with significant downregulation of both Ser 675‐phosphorylated β‐catenin and its target genes, cyclin D1 and survivin. However, the molecular mechanism responsible for its cytotoxic effect has not yet been fully characterized. In the present study, we demonstrated that NC114 prevented cell cycle progression from S to G2/M phase by downregulating cell cycle‐related gene expression, and also induced growth arrest in SW480 and HCT‐116 colorectal cancer cells. A novel covariation network analysis combined with transcriptome analysis revealed a series of signaling cascades affected by NC114 treatment, and identified protein kinase C‐δ (PKCδ) and forkhead box protein M1 (FOXM1) as important regulatory factors for NC114‐induced growth arrest. NC114 treatment inhibits the activation of PKCδ and its kinase activity, which suppresses MEK/ERK signaling. Attenuated MEK/ERK signaling then results in a reduction in FOXM1 phosphorylation and subsequent nuclear translocation of FOXM1 and β‐catenin. Consequently, formation of a T‐cell factor‐4 (TCF4)/β‐catenin transcription complex in the nucleus is inhibited and transcription of its target genes, such as cell cycle‐related genes, is downregulated. The efficacy of NC114 on tumor growth was confirmed in a xenograft model. Collectively, elucidation of the mechanism by which NC114 induces growth arrest in colorectal cancer cells should provide a novel therapeutic strategy for colorectal cancer treatment. [ABSTRACT FROM AUTHOR]

Cucurbitacin C (CuC), a novel analogue of triterpenoids cucurbitacins, confers a bitter taste in cucumber. Genes and signaling pathways responsive for biosynthesis of CuC have been identified in the recent years. In the present study, we explored the anti-cancer effects of CuC against human cancers in vitro and in vivo. CuC inhibited proliferation and clonogenic potential of multiple cancer cells in a dose-dependent manner. Lowdose CuC treatment induced cell cycle arrest at G1 or G2/M stage in different cancer lines, whereas high-dose treatment of CuC caused apoptosis in cancer cells. PI3KAkt signaling pathway was found to be one of the major pathways involved in CuC-induced cell growth arrest and apoptosis by RNA-Seq and Western blotting. Mechanistic dissection further confirmed that CuC effectively inhibited the Akt signaling by inhibition of Akt phosphorylation at Ser473. In vivo CuC treatment (0.1 mg/kg body weight) effectively inhibited growth of cancer cell-derived xenograft tumors in athymic nude mice and caused significant apoptosis. Our findings for the first time demonstrated the potential therapeutic significance of CuC against human cancers. [ABSTRACT FROM AUTHOR]

Quiescence, the temporary and reversible arrest of cell growth, is a fundamental biological process. However, the lack of standardization in terms of reporting the experimental details of quiescent cells and populations can cause confusion and hinder knowledge transfer. We employ the systematic review methodology to comprehensively analyze the diversity of approaches used to study the quiescent state, focusing on all published research addressing the budding yeast Saccharomyces cerevisiae. We group research articles into those that consider all cells comprising the stationary-phase (SP) population as quiescent and those that recognize heterogeneity within the SP by distinguishing phenotypically distinct subpopulations. Furthermore, we investigate the chronological age of the quiescent populations under study and the methods used to induce the quiescent state, such as gradual starvation or abrupt environmental change. We also assess whether the strains used in research are prototrophic or auxotrophic. By combining the above features, we identify 48 possible experimental setups that can be used to study quiescence, which can be misleading when drawing general conclusions. We therefore summarize our review by proposing guidelines and recommendations pertaining to the information included in research articles. We believe that more rigorous reporting on the features of quiescent populations will facilitate knowledge transfer within and between disciplines, thereby stimulating valuable scientific discussion. [ABSTRACT FROM AUTHOR]

Abstract Background In the treatment of tall stature, the reduction of excessive predicted final height can either be achieved by hormonal treatment or surgically by temporary (tED) or permanent (pED) epiphysiodesis. The present study evaluates the preliminary results of two novel devices for tED and pED around the knee to reduce the predicted final height. Materials and methods A retrospective analysis was performed to evaluate the clinical and radiographic outcome after bilateral epiphysiodesis for the treatment of tall stature. A cohort of 34 patients (16 girls, 18 boys) who underwent either tED or pED between 2015 and 2020 were eligible for analysis based on the electronic patient records and picture archiving and communication system of our orthopaedic teaching hospital. tED was conducted in 11 patients (32%) through bilateral implantation of four RigidTacks™ (Merete, Berlin, Germany) around the knee. Twenty-three patients (68%) received pED, performed with an EpiStop™ trephine (Eberle, Wurmberg, Germany). The mean overall follow-up time was 2.9 years. Results The mean age at surgery was 12.3 years in girls and 13.2 years in boys. Patients had a mean body height of 175.2 cm in girls and 184.7 cm in boys at surgery. The mean predicted final height was 191.4 cm in girls and 210.4 cm in boys. At the last follow-up, 26 patients (76.5%) had achieved skeletal maturity. The mean height of skeletally mature patients was 187.2 cm in girls and 198.5 cm in boys. A mean reduction of the predicted final height of 5.9 cm in girls and 8.7 cm in boys was achieved, corresponding to a reduction in remaining growth of 46% in girls and 38% in boys. Secondary frontal plane deformities of the knee were detected in 5/11 patients (45.5%) in the tED group and 1/23 treatments (4.3%) in the pED group. Conclusions tED and pED have both proven to be efficient at achieving growth inhibition to reduce excessive predicted height. However, tED has been associated with an increased risk of secondary angular deformities of the knee. Furthermore, the risk of implant-related complications and the necessity of a subsequent surgical intervention for implant removal have led our study group to abandon tED when treating tall stature. Long-term results of both procedures are pending. Level of evidence 4.

Background and purpose: Premature physeal closure (PPC) is a common and concerning complication to distal femoral fractures as the distal growth plate accounts for 70% of the growth of the femur. The literature is not unanimous in determining the risk factors of PPC, and the epidemiological characterization of these fractures is limited. Our aim was to calculate the population-based incidence and investigate risk factors for PPC in these fractures. Patients and methods: In this register-based study, between 2014 and 2021, 70 children with distal femoral physeal fractures presented to our hospital. Demographic data, and fracture- and treatment-related details were collected using the Kids’ Fracture Tool. A directed acyclic graph (DAG) was constructed to determine confounding factors used in the risk analysis. Results: Physeal fractures of the distal femur occurred with an annual incidence of 6/105 children, and a resulting PPC occurred in 16/70 (23%) with an annual incidence of 1.3/105 children. In multivariable analysis, dislocation exceeding 10 mm was a risk factor for PPC (OR 6.3, CI 1.4-22). Conclusion: One-fourth of distal femoral physeal fractures developed PPC. Greater dislocation and higher injury energy were significant risk factors, whereas choice of fracture treatment was not an independent risk factor. All patients with PPC belonged in the age group 11–16 years.

Background and purpose: Physeal fractures represent 15–20% of all pediatric fractures and may lead to premature physeal closure (PPC). The aim of our study was to determine the incidence rates of physeal fractures in the lower limb and the proportion of PPC that lead to limb length discrepancy (LLD), and/or angular deformity (AD). Patients and methods: This retrospective study included 236 consecutive children with physeal fracture in the tibia, distal femur, or distal fibula. We estimated incidence rates and reviewed medical records and radiographs to obtain information regarding the development of PPC leading to LLD and AD. Of the 236 children, 100 had planned growth control or were referred for growth control due to symptoms of PPC. Results: The total incidence rate was 35 (95% CI 30–39) per 100,000 person-years, with 1.2 (CI 0.5–23) for distal femur, 5.7 (CI 3.1–7.8) for proximal tibia, 14 (CI 11–17) for distal tibia, and 14 (CI 11–17) for distal fibula. The overall prevalence of PPC was 9.7% (CI 6.3–14), while the prevalence was 38% (CI 8.5–76) for distal femur, 15% (CI 5.9–31) for proximal tibia, 14% (CI 7.4-–22) for distal tibia, and 1.1% (CI 0.3-–59) for distal fibula. We found a significant higher hazard of PPC in fractures with ≥ 3 mm displacement (hazard ratio: 12, CI 1.5–97). Conclusion: 10% of children with physeal fractures developed PPC that led to LLD or AD. The highest hazard ratio was in children who had an initial fracture displacement. This study highlights the importance of routine and uniform growth evaluation after a physeal fracture

ABSTRACT c-di-GMP primarily controls motile to sessile transitions in bacteria. Diguanylate cyclases (DGCs) catalyze the synthesis of c-di-GMP from two GTP molecules. Typically, bacteria encode multiple DGCs that are activated by specific environmental signals. Their catalytic activity is modulated by c-di-GMP binding to autoinhibitory sites (I-sites). YfiN is a conserved inner membrane DGC that lacks these sites. Instead, YfiN activity is directly repressed by periplasmic YfiR, which is inactivated by redox stress. In Escherichia coli, an additional envelope stress causes YfiN to relocate to the mid-cell to inhibit cell division by interacting with the division machinery. Here, we report a third activity for YfiN in E. coli, where cell growth is inhibited without YfiN relocating to the division site. This action of YfiN is only observed when the bacteria are cultured on gluconeogenic carbon sources, and is dependent on absence of the autoinhibitory sites. Restoration of I-site function relieves the growth-arrest phenotype, and disabling this function in a heterologous DGC causes acquisition of this phenotype. Arrested cells are tolerant to a wide range of antibiotics. We show that the likely cause of growth arrest is depletion of cellular GTP from run-away synthesis of c-di-GMP, explaining the dependence of growth arrest on gluconeogenic carbon sources that exhaust more GTP during production of glucose. This is the first report of c-di-GMP-mediated growth arrest by altering metabolic flow. IMPORTANCE The c-di-GMP signaling network in bacteria not only controls a variety of cellular processes such as motility, biofilms, cell development, and virulence, but does so by a dizzying array of mechanisms. The DGC YfiN singularly represents the versatility of this network in that it not only inhibits motility and promotes biofilms, but also arrests growth in Escherichia coli by relocating to the mid-cell and blocking cell division. The work described here reveals that YfiN arrests growth by yet another mechanism in E. coli, changing metabolic flow. This function of YfiN, or of DGCs without autoinhibitory I-sites, may contribute to antibiotic tolerant persisters in relevant niches such as the gut where gluconeogenic sugars are found.

ABSTRACT Almost all bactericidal drugs require bacterial replication and/or metabolic activity for their killing activity. When these processes are inhibited by bacteriostatic antibiotics, bacterial killing is significantly reduced. One notable exception is the lipopeptide antibiotic daptomycin, which has been reported to efficiently kill growth-arrested bacteria. However, these studies employed only short periods of growth arrest (

ABSTRACT As rapidly growing bacteria begin to exhaust essential nutrients, they enter a state of reduced growth, ultimately leading to stasis or quiescence. Investigation of the response to nutrient limitation has focused largely on the consequences of amino acid starvation, known as the “stringent response.” Here, an uncharged tRNA in the A-site of the ribosome stimulates the ribosome-associated protein RelA to synthesize the hyperphosphorylated guanosine nucleotides (p)ppGpp that mediate a global slowdown of growth and biosynthesis. Investigations of the stringent response typically employ experimental methodologies that rapidly stimulate (p)ppGpp synthesis by abruptly increasing the fraction of uncharged tRNAs, either by explicit amino starvation or by inhibition of tRNA charging. Consequently, these methodologies inhibit protein translation, thereby interfering with the cellular pathways that respond to nutrient limitation. Thus, complete and/or rapid starvation is a problematic experimental paradigm for investigating bacterial responses to physiologically relevant nutrient-limited states.

The establishment of Mycobacterium tuberculosis (Mtb) long-term infection in vivo depends on several factors, one of which is the availability of key nutrients such as iron (Fe). The relation between Fe deprivation inside and outside the granuloma, and the capacity of Mtb to accumulate lipids and persist in the absence of growth is not well understood. In this context, current knowledge of how Mtb modifies its lipid composition in response to growth arrest, depending on iron availability, is scarce. To shed light on these matters, in this work we compare genome-wide transcriptomic and lipidomic profiles of Mtb at exponential and stationary growth phases using cultures with glycerol as a carbon source, in the presence or absence of iron. As a result, we found that transcriptomic responses to growth arrest, considered as the transition from exponential to stationary phase, are iron dependent for as many as 714 genes (iron-growth interaction contrast, FDR <0.05), and that, in a majority of these genes, iron deprivation enhances the magnitude of the transcriptional responses to growth arrest in either direction. On the one hand, genes whose upregulation upon growth arrest is enhanced by iron deprivation were enriched in functional terms related to homeostasis of ion metals, and responses to several stressful cues considered cardinal features of the intracellular environment. On the other hand, genes showing negative responses to growth arrest that are stronger in iron-poor medium were enriched in energy production processes (TCA cycle, NADH dehydrogenation and cellular respiration), and key controllers of ribosomal activity shut-down, such as the T/A system mazE6/F6. Despite of these findings, a main component of the cell envelope, lipid phthiocerol dimycocerosate (PDIM), was not detected in the stationary phase regardless of iron availability, suggesting that lipid changes during Mtb adaptation to non-dividing phenotypes appear to be iron-independent. Taken together, our results indicate that environmental iron levels act as a key modulator of the intensity of the transcriptional adaptations that take place in the bacterium upon its transition between dividing and dormant-like phenotypes in vitro. [ABSTRACT FROM AUTHOR]

Background: In the treatment of tall stature, the reduction of excessive predicted final height can either be achieved by hormonal treatment or surgically by temporary (tED) or permanent (pED) epiphysiodesis. The present study evaluates the preliminary results of two novel devices for tED and pED around the knee to reduce the predicted final height.Materials and Methods: A retrospective analysis was performed to evaluate the clinical and radiographic outcome after bilateral epiphysiodesis for the treatment of tall stature. A cohort of 34 patients (16 girls, 18 boys) who underwent either tED or pED between 2015 and 2020 were eligible for analysis based on the electronic patient records and picture archiving and communication system of our orthopaedic teaching hospital. tED was conducted in 11 patients (32%) through bilateral implantation of four RigidTacks™ (Merete, Berlin, Germany) around the knee. Twenty-three patients (68%) received pED, performed with an EpiStop™ trephine (Eberle, Wurmberg, Germany). The mean overall follow-up time was 2.9 years.Results: The mean age at surgery was 12.3 years in girls and 13.2 years in boys. Patients had a mean body height of 175.2 cm in girls and 184.7 cm in boys at surgery. The mean predicted final height was 191.4 cm in girls and 210.4 cm in boys. At the last follow-up, 26 patients (76.5%) had achieved skeletal maturity. The mean height of skeletally mature patients was 187.2 cm in girls and 198.5 cm in boys. A mean reduction of the predicted final height of 5.9 cm in girls and 8.7 cm in boys was achieved, corresponding to a reduction in remaining growth of 46% in girls and 38% in boys. Secondary frontal plane deformities of the knee were detected in 5/11 patients (45.5%) in the tED group and 1/23 treatments (4.3%) in the pED group.Conclusions: tED and pED have both proven to be efficient at achieving growth inhibition to reduce excessive predicted height. However, tED has been associated with an increased risk of secondary angular deformities of the knee. Furthermore, the risk of implant-related complications and the necessity of a subsequent surgical intervention for implant removal have led our study group to abandon tED when treating tall stature. Long-term results of both procedures are pending.Level Of Evidence:4: [ABSTRACT FROM AUTHOR]

Case: An 11-year-old Caucasian boy presented to the emergency department with a displaced, closed, Galeazzi equivalent (GE) left wrist fracture sustained after a fall. Closed reduction was deemed unsatisfactory because of persistent displacement of the distal ulna epiphysis. An open reduction of the distal ulna and percutaneous fracture pinning was performed. At 1 year, the patient reported return to his preinjury baseline. No evidence of subsequent pathologic growth was detected on follow-up imaging. Conclusion: Open anatomic reduction of the distal ulna epiphysis and percutaneous fracture pinning may improve patient outcomes and limit progressive wrist deformity when treating GE wrist injuries. [ABSTRACT FROM AUTHOR]

The establishment of Mycobacterium tuberculosis (Mtb) long-term infection in vivo depends on several factors, one of which is the availability of key nutrients such as iron (Fe). The relation between Fe deprivation inside and outside the granuloma, and the capacity of Mtb to accumulate lipids and persist in the absence of growth is not well understood. In this context, current knowledge of how Mtb modifies its lipid composition in response to growth arrest, depending on iron availability, is scarce. To shed light on these matters, in this work we compare genome-wide transcriptomic and lipidomic profiles of Mtb at exponential and stationary growth phases using cultures with glycerol as a carbon source, in the presence or absence of iron. As a result, we found that transcriptomic responses to growth arrest, considered as the transition from exponential to stationary phase, are iron dependent for as many as 714 genes (iron-growth interaction contrast, FDR

Quiescence, the temporary and reversible arrest of cell growth, is a fundamental biological process. However, the lack of standardization in terms of reporting the experimental details of quiescent cells and populations can cause confusion and hinder knowledge transfer. We employ the systematic review methodology to comprehensively analyze the diversity of approaches used to study the quiescent state, focusing on all published research addressing the budding yeast Saccharomyces cerevisiae. We group research articles into those that consider all cells comprising the stationary-phase (SP) population as quiescent and those that recognize heterogeneity within the SP by distinguishing phenotypically distinct subpopulations. Furthermore, we investigate the chronological age of the quiescent populations under study and the methods used to induce the quiescent state, such as gradual starvation or abrupt environmental change. We also assess whether the strains used in research are prototrophic or auxotrophic. By combining the above features, we identify 48 possible experimental setups that can be used to study quiescence, which can be misleading when drawing general conclusions. We therefore summarize our review by proposing guidelines and recommendations pertaining to the information included in research articles. We believe that more rigorous reporting on the features of quiescent populations will facilitate knowledge transfer within and between disciplines, thereby stimulating valuable scientific discussion.

Salinomycin (SAL) is a monocarboxylic polyether ionophore antibiotic isolated from Streptomyces albus. It exhibits an effective antitumor potential against numerous human cancer cells. This study aimed to assess the antiproliferative effects of SAL in human hepatocellular carcinoma HepG2/C3a cell line. We investigated the effects of SAL on cell growth, DNA damage induction, cell cycle changes and apoptosis; and relative changes in expression of cell cycle-related, apoptosis-related, and CYP450 genes. SAL induced cell cycle arrest in the G2/M phase, upregulation of CDKN1A and GADD45A and downregulation of cyclin genes including CCNB1 and CCNA2. SAL effectively suppressed mRNA levels of CTNNB1 gene, an important oncogene that promotes tumorigenesis. The decrease of HepG2/C3A cells' survival can also be due to downregulation of antiapoptotic BCL-2 expression, thus promoting the induction of apoptosis by SAL. This study also demonstrated the ability of SAL in modulating hepatic cytochrome P450 (CYP) mRNA expression, such that SAL caused the upregulation of CYP1A members and CYP3A5; and downregulation of CYP3A4. Taken together, these data contribute to the understanding of the mechanism of action of SAL, highlighting that metabolizing enzymes modulated by SAL can interfere with chemotherapy treatment and it must be considered in associated treatments. [ABSTRACT FROM AUTHOR]

Partial physeal bars may develop after injury to the growth plate in children, eventually leading to disturbance of normal growth. Clinical presentation, age of the patient, and the anticipated growth will dictate the best treatment strategy. The ideal treatment for a partial physeal bar is complete excision to allow growth resumption by the remaining healthy physis. There are countless surgical options, some technically challenging, that must be weighted according to each case’s particularities. We reviewed the current literature on physeal bars while reporting the challenging case of a short stature child submitted to a femoral physeal bar endoscopic-assisted resection with successful growth resumption. This case dares surgeons to consider all options when treating limb length discrepancy, such as the endoscopic-assisted resection which might offer successful results.

We present an unusual Mexican patient affected with mucopolysaccharidosis type IIIB (MPS IIIB; also called Sanfilippo B syndrome, MIM #252920) bearing clinical features that have not previously been described for MPS IIIB (growth arrest, hypogonadotropic hypogonadism, and congenital heart disease). Chromosomal microarray analysis was useful in identifying runs of homozygosity at 17q11.1–q21.33 and supporting the diagnosis of an underlying autosomal recessive condition. Sanger sequencing of NAGLU (17q21.2, MIM*609701) allowed us to identify a pathogenic homozygous p.(Arg234Cys) genotype. This NAGLU allele could be related to that previously described in an Iberian MPS IIIB founder haplotype; results from the polymorphic marker D17S800 and rs2071046 led us to hypothesize that it may have been introduced to Mexico through the Spanish settlement. The analysis of a clinical exome sequencing ruled out other monogenic etiologies for the previously undescribed clinical MPS IIIB manifestations. Our findings contribute to further delineating the MPS IIIB phenotype and suggest possible phenotype–genotype correlations. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite tremendous treatment efforts, cancer is still one of the leading causes of death, with approximately 10 million deaths in 2020. In the last decade, immunotherapy entered the stage of clinical practice and was added to the established regimen, i.e., surgery, chemo- and radiation therapy, to fight this deadly disease. Cancer immunotherapies, including immune checkpoint inhibitors, target malignant cancer cells and immune cells in the tumor micro-environment. Among those cells are T cells and antigen-presenting cells, which can efficiently control tumors via both cell-cell interactions and by secretion of inflammatory cytokines. The presence of specific cytokines in the tumor microenvironment has been shown to induce senescence in tumor cells. Subsequently, tumor cells acquire a senescence-associated secretory phenotype that strongly modulates anti-tumor responses. This review describes the mechanisms of cytokine-induced senescence in the tumor microenvironment and highlights their relevance for therapeutic perspectives. In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system's ability to establish "defensive walls" around tumors also places the tumor microenvironment into the fight against cancer. Those "defensive walls" isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease. [ABSTRACT FROM AUTHOR]

Paediatric bone and joint infections can be associated with devastating consequences for the growing child. The diagnosis is challenging, requiring experienced clinical examination with adjunct diagnostic tests to aid the distinction between a multitude of differential diagnoses which includes transient synovitis, fracture, neoplasia, rheumatological conditions, blood disorders and infection. Emergent diagnosis is required to prevent consequences such as sepsis, chronic infection, angular deformity and disruption of longitudinal bone growth. The clinical presentation of bone and joint infections in children is varied and includes pain, erythema and swelling, fever, reduced range of movement and the inability to weight bear. Blood and tissue samples should be obtained, if possible, prior to commencing antimicrobial therapy in order to secure the best chance of identifying a causative organism and guide treatment. However, this should not delay treatment. Various imaging modalities can be helpful. Whilst there is some variation depending on the child's age, Staphylococcus aureus is the commonest causative organism in both septic arthritis and osteomyelitis. Septic arthritis and osteomyelitis in children should be treated jointly by paediatricians and orthopaedic surgeons, with input from the wider multi-disciplinary team. Trends towards reduced rates of surgical intervention and shorter antibiotic courses have been evident over recent decades. In this article we present a review of the continuously evolving concepts for the management of paediatric bone and joint infections. [ABSTRACT FROM AUTHOR]

Abstract Background Mortalin is enriched in a large variety of cancers and has been shown to contribute to proliferation and migration of cancer cells in multiple ways. It has been shown to bind to p53 protein in cell cytoplasm and nucleus causing inactivation of its tumor suppressor activity in cancer cells. Several other activities of mortalin including mitochondrial biogenesis, ATP production, chaperoning, anti-apoptosis contribute to pro-proliferative and migration characteristics of cancer cells. Mortalin-compromised cancer cells have been shown to undergo apoptosis in in vitro and in vivo implying that it could be a potential target for cancer therapy. Methods We implemented a screening of a chemical library for compounds with potential to abrogate cancer cell specific mortalin-p53 interactions, and identified a new compound (named it as Mortaparib) that caused nuclear enrichment of p53 and shift in mortalin from perinuclear (typical of cancer cells) to pancytoplasmic (typical of normal cells). Biochemical and molecular assays were used to demonstrate the effect of Mortaparib on mortalin, p53 and PARP1 activities. Results Molecular homology search revealed that Mortaparib is a novel compound that showed strong cytotoxicity to ovarian, cervical and breast cancer cells. Bioinformatics analysis revealed that although Mortaparib could interact with mortalin, its binding with p53 interaction site was not stable. Instead, it caused transcriptional repression of mortalin leading to activation of p53 and growth arrest/apoptosis of cancer cells. By extensive computational and experimental analyses, we demonstrate that Mortaparib is a dual inhibitor of mortalin and PARP1. It targets mortalin, PARP1 and mortalin-PARP1 interactions leading to inactivation of PARP1 that triggers growth arrest/apoptosis signaling. Consistent with the role of mortalin and PARP1 in cancer cell migration, metastasis and angiogenesis, Mortaparib-treated cells showed inhibition of these phenotypes. In vivo tumor suppression assays showed that Mortaparib is a potent tumor suppressor small molecule and awaits clinical trials. Conclusion These findings report (i) the discovery of Mortaparib as a first dual inhibitor of mortalin and PARP1 (both frequently enriched in cancers), (ii) its molecular mechanism of action, and (iii) in vitro and in vivo tumor suppressor activity that emphasize its potential as an anticancer drug.

Introduction: Distal radius fractures account for nearly one-third of all pediatric fractures, making it among the most common of all pediatric fractures. Studies report that distal radius physeal arrest rates following trauma to the distal radius seem to occur in only about 5% of patients. Significant ulnar variance can develop leading to notable pain and limitations in function., Case Report: We present a case of a 17-year-old right-hand dominant adolescent Caucasian male with persistent ulnar wrist pain. The patient presented to our outpatient clinic for evaluation of his left wrist following 6-8 months of persistent ulnar-sided pain. Ten months prior, the patient had fallen off a shed and was treated in the emergency room and referred to the outpatient clinic for follow-up. The patient initially sustained a Salter-Harris Type 2 distal radius fracture treated with closed reduction and short arm cast application in the emergency room. The short arm cast was removed at 8 weeks, and then, the patient was placed in a brace. The patient was lost to follow-up before returning to the clinic 16 months after the original injury when he noticed worsening pain in the left wrist, localized to the distal radioulnar joint with increased hand usage at a new job. Radiographs at that time showed a worsening positive ulnar variance as well as a partially open distal ulnar physis. After 6 months of occupational therapy and over-the-counter pain management, the ulnar-sided pain had not resolved. The radiograph showed a positive Ulna variance of 2.5 mm, which was corrected with a 5 mm excision osteotomy of the distal ulna. The patient reported significant pain relief and a 42-point improvement in his patient-rated wrist evaluation score., Conclusion: Distal radius growth arrest, while uncommon, can present with ulnar-sided pain and positive ulnar variance that is safely treatable with ulnar shortening osteotomy., Competing Interests: Conflict of Interest: Nil, (Copyright: © Indian Orthopaedic Research Group.)

Key message: This study focused on the key regulatory function of Physcomitrium patens GRAS12 gene underlying an increasing plant complexity, an important step in plant terrestrialization and the evolutionary history of life. The miR171‐GRAS module has been identified as a key player in meristem maintenance in angiosperms. PpGRAS12 is a member of the GRAS family and a validated target for miR171 in Physcomitrium (Physcomitrella) patens. Here we show a regulatory function of miR171 at the gametophytic vegetative growth stage and targeted deletion of the PpGRAS12 gene adversely affects sporophyte production since fewer sporophytes were produced in ΔPpGRAS12 knockout lines compared to wild type moss. Furthermore, highly specific and distinct growth arrests were observed in inducible PpGRAS12 overexpression lines at the protonema stage. Prominent phenotypic aberrations including the formation of multiple apical meristems at the gametophytic vegetative stage in response to elevated PpGRAS12 transcript levels were discovered via scanning electron microscopy. The production of multiple buds in the PpGRAS12 overexpression lines similar to ΔPpCLV1a/1b disruption mutants is accompanied by an upregulation of PpCLE and downregulation of PpCLV1, PpAPB, PpNOG1, PpDEK1, PpRPK2 suggesting that PpGRAS12 acts upstream of these genes and negatively regulates the proposed pathway to specify simplex meristem formation. As CLV signaling pathway components are not present in the chlorophytic or charophytic algae and arose with the earliest land plants, we identified a key regulatory function of PpGRAS12 underlying an increasing plant complexity, an important step in plant terrestrialization and the evolutionary history of life. [ABSTRACT FROM AUTHOR]

Background: Fractures through the physis account for 18–30% of paediatric fractures and can lead to growth arrest in 5–10% of these cases. Long-term radiographic follow-up is usually necessary to monitor for signs of growth arrest at the affected physis. Given plain radiographs of a physeal fracture obtained throughout patient follow-up, different surgeons may hold different opinions about whether or not early growth arrest has occurred despite using identical radiographs to guide decision-making. This study aims to assess the inter-rater and intra-rater reliability of early growth arrest diagnosis among orthopaedic surgeons given a set of identical plain radiographs. Methods: A retrospective chart review was conducted on patients aged 2–18 years previously treated for a physeal fracture at a paediatric tertiary care hospital between 2011 and 2018. De-identified anteroposterior (AP) and lateral radiographs of 39 patients from the date of injury and minimum one-year post-injury were administered in a survey to international paediatric orthopaedic surgeons. Each surgeon was asked whether they would diagnose the patient with growth arrest based on the radiographs provided. Surgeons were asked to complete this process again two weeks after the initial review, but using identical shuffled radiographs. Inter-rater and intra-rater reliability was calculated using appropriate kappa statistics. Results: A total of 11 paediatric orthopaedic surgeons completed the first round of the survey, and 9 of these 11 completed the second round. The inter-rater reliability for the first round was 0.22 [95% CI (0.06, 0.35)] and 0.21 [95% CI (0.02, 0.32)] for the second round. The average kappa for intra-rater reliability was − 0.05 [95% CI (− 0.31, 0.21)]. Comparison by injury side showed no significant variation in diagnosis {p = 0.509, OR = 0.90, [95% CI (0.67, 1.22)]}, while comparison by location of injury varied significantly (p = 0.003). Conclusions: Radiographic diagnosis of growth arrest among paediatric orthopaedic surgeons demonstrated 'fair' inter-rater agreement and no intra-rater agreement, suggesting critical differences in identifying growth arrest on plain radiographs. Further research is necessary to develop an improved diagnostic approach for growth arrest among orthopaedic surgeons. Level of Evidence: Diagnostic level III. [ABSTRACT FROM AUTHOR]

Context: Children with anorexia nervosa (AN) are at risk of adult height deficit due to prolonged low height velocity (HV).Objective: To investigate the effects of human growth hormone (GH) injections on HV in children with AN and severe growth impairment.Design and Participants: In this prospective, randomized, double-blind, single-center, proof-of-concept trial, children with AN and low HV (≤2 cm/year) for at least 18 months, and a bone age ≤12 years for girls and ≤14 years for boys, were randomized to receive daily subcutaneous injections of human GH (0.050 mg/kg/day) or placebo for 12 months.Main Outcome Measures: Change in HV after 12 months.Results: In total, 8 patients were assigned to the GH group and 6 to the placebo group. Patients had a median (25th-75th percentile) HV of 1.0 (0.5;1.5) cm/year. The effect of GH treatment increased strongly after 6 months, with a height gain after 12 months of 9.65 (8.0;11.6) cm for the GH group vs 3.85 (1.7;7.3) cm for the placebo group, with an absolute median (2.5th-97.5th percentile) difference between the groups of 5.8 (-1.85;9.68) cm after bootstrapping. The percentage of patients with a HV > 5 cm/year during the study period was higher in the GH group than in the placebo group (100% vs 50%, P = 0.05). Adverse events occurred in similar numbers in the 2 groups, were mild or nonfatal, and did not lead to treatment being stopped.Conclusion: GH administration to improve HV is a potentially valid option for increasing HV in children with AN and prolonged severe growth failure. [ABSTRACT FROM AUTHOR]

The multitasking promyelocytic leukemia (PML) protein was originally recognized as a tumor‐suppressive factor, but more recent evidence has implicated PML in tumor cell prosurvival actions and poor patient prognosis in specific cancer settings. Here, we report that inducible PMLIV expression inhibits cell proliferation as well as self‐renewal and impairs cell cycle progression of breast cancer cell lines in a reversible manner. Transcriptomic profiling identified a large number of PML‐deregulated genes associated with various cell processes. Among them, cell cycle‐ and division‐related genes and their cognitive regulators are highly ranked. In this study, we focused on previously unknown PML targets, namely the Forkhead transcription factors. PML suppresses the Forkhead box subclass M1 (FOXM1) transcription factor at both the RNA and protein levels, along with many of its gene targets. We show that FOXM1 interacts with PMLIV primarily via its DNA‐binding domain and dynamically colocalizes in PML nuclear bodies. In parallel, PML modulates the activity of Forkhead box O3 (FOXO3), a factor opposing certain FOXM1 activities, to promote cell survival and stress resistance. Thus, PMLIV affects the balance of FOXO3 and FOXM1 transcriptional programs by acting on discrete gene subsets to favor both growth inhibition and survival. Interestingly, PMLIV‐specific knockdown mimicked ectopic expression vis‐à‐vis loss of proliferative ability and self‐renewal, but also led to loss of survival ability as shown by increased apoptosis. We propose that divergent or similar effects on cell physiology may be elicited by high or low PMLIV levels dictated by other concurrent genetic or epigenetic cancer cell states that may additionally account for its disparate effects in various cancer types.

Background: Posttraumatic distal radius growth arrest is a challenging orthopedic condition, due to a combination of several deformity components including shortening, angulation and joint line malorientation. It can drastically affect both the function and the shape of the wrist and forearm. However, little has been written about this problem. Patients and Methods: In this retrospective study, seven adolescent patients were operated in our department. All had posttraumatic distal radius growth arrest that resulted in shortening with or without angular deformity. The management consisted of distal radius metaphyseal osteotomy and distraction osteogenesis using Ilizarov frame. The patients' ages ranged from 12 to 15 years. The mean shortening of the radius was 2.2 cm. Correction was assessed radiologically (radial length, joint orientation line) and clinically by Mayo Wrist Score. Results: The mean external fixation time was 2.4 months (range from 2 to 3 months). The mean total treatment time was 12.3 weeks (range from 12 to 16 weeks). The mean bone healing index was 1.13 months/cm. The Mayo Wrist Score mean was 85.7 (range: 75–95) points. According to the Mayo Wrist Score, results were excellent in three patients, good in three patients, satisfactory in one patient with no unsatisfactory results. Superficial pin tract infection occurred in all cases and was managed without further sequelae. Conclusion: Distraction osteogenesis, by Ilizarov external fixator, addresses the sequelae of posttraumatic distal radius growth arrest by restoring the normal anatomy in a controlled biological manner, without further grafting procedures through a minimally invasive approach.

Background: . This study performed to investigate the incidence of growth arrest such as leg length discrepancy (LLD) and ankle joint angular deformity and its risk factors after physeal fracture of the distal tibia in children and adolescents.Materials and Methods: . Consecutive 78 patients (mean age 11.4 ± 2.0 years; mean follow-up period 2.0 ± 1.2 years) treated for the distal tibia physeal fracture were included. All patients underwent preoperative ankle radiographs, three-dimensional computed tomography (CT) scans, and postoperative follow-up teleradiogram. Patients were divided into two groups according to the LLD and the difference of lateral distal tibial angle (LDTA) with the contralateral limb as follows: Group 1 (growth arrest), patients with LLD ≥ 1cm or difference of LDTA ≥ 5°; Group 2 (normal growth), patients with LLD < 1cm and difference of LDTA < 5°.Results: . The overall incidence of growth arrest was 12.8% (10 of 78). The mean displacement measured using CT scan was 4.4 ± 3.2 mm (range, 0.8-14.9). Of the total 78 fractures, 65 were treated surgically and 13 fractures were treated conservatively. The initial fracture displacement was significantly different between the two groups (p<0.001). However, there were no statistically significant differences between the two groups with respect to other factors. Initial displacement was the only significant risk factor for growth arrest (p<0.003). The cutoff values of initial displacement between the two groups were 5.2mm.Conclusions: . This study showed that degree of initial displacement was the only significant risk factor for growth arrest after physeal fracture of the distal tibia in children and adolescents. Therefore, physicians should consider the possibility of growth arrest for patients with severely displaced physeal fractures of the distal tibia. [ABSTRACT FROM AUTHOR]

Heterotrophic Proteobacteria are versatile opportunists that have been extensively studied as model organisms in the laboratory, as both pathogens and beneficial symbionts of plants and animals, and as ubiquitous organisms found freeliving in many environments. Succeeding in these niches requires an ability to persist for potentially long periods of time in growth-arrested states when essential nutrients become limiting. The tendency of these bacteria to grow in dense biofilm communities frequently leads to the development of steep nutrient gradients and deprivation of interior cells even when the environment is nutrient rich. Surviving within host environments also likely requires tolerating growth arrest due to the host limiting access to nutrients and transitioning between hosts may require a period of survival in a nutrient-poor environment. Interventions to maximise plant-beneficial activities and minimise infections by bacteria will require a better understanding of metabolic and regulatory networks that contribute to starvation survival, and how these networks function in diverse organisms. Here we focus on carbon starvation as a growth-arresting condition that limits availability not only of substrates for biosynthesis but also of energy for ongoing maintenance of the electrochemical gradient across the cell envelope and cellular integrity. We first review models for studying bacterial starvation and known strategies that contribute to starvation survival. We then present the results of a survey of carbon starvation survival strategies and outcomes in ten bacterial strains, including representatives from the orders Enterobacterales and Pseudomonadales (both Gammaproteobacteria) and Burkholderiales (Betaproteobacteria). Finally, we examine differences in gene content between the highest and lowest survivors to identify metabolic and regulatory adaptations that may contribute to differences in starvation survival. [ABSTRACT FROM AUTHOR]

It is widely accepted that there exists a "resting" or "quiescent" state where a growing cell leaves the cell cycle to enter what is often called the "G0‐phase." I propose that there is no biological reality to the "G0‐phase." The experimental basis for proposing a G0‐phase is re‐examined and re‐analyzed here showing that the G0‐phase is an anthropomorphic construct with no biological reality. [ABSTRACT FROM AUTHOR]