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Redispersible polystyrene (PS) latexes with particle sizes in the range of 250 nm were prepared using low-molecular-weight amphiphilic thermoresponsive polymeric surfactants. A series of linear polymers with cetyl/stearyl as hydrophobic part and poly(2-methyloxazoline)/poly(2- ethyloxazoline) with about ten repeat units were synthesized through cationic ring opening polymerization (CROP) and were used as nonionic surfactants (NIS) in the preparation of poly(styrene) latexes by batch emulsion polymerization. Latexes prepared with surfactant containing thermoresponsive segments upon being heated yielded a white coagulant above its LCST temperature at 85 oC and redispersed upon cooling with minimal stirring. The particle sizes measured at 25 oC confirmed that the pristine and redispersed latex had almost similar size, whereas at 85 oC an abrupt change in the particle sizes were observed. This promising result shows the excellent use of thermoresponsive surfactant for the preparation of readily redispersible polystyrene latexes.

Background: Baseline HER3 protein or ERBB3 mRNA levels do not seem to predict efficacy from HER3-DXd in early-stage and advanced HR+/HER2- breast cancer (Prat et al. ESMO Breast 2022; Krop et al. ASCO 2022). Here, we evaluated potential baseline pre-treatment genetic determinants of efficacy to HER3-DXd. Methods: SOLTI TOT-HER3 (NCT04610528) is a window of opportunity, multicenter, pre-operative trial which enrolled, in part A, 77 evaluable patients with untreated HR+/HER2- operable (≥1 cm) breast cancer. Patients received a single dose of HER3-DXd (6.4 mg/kg). The primary objective was to evaluate the CelTIL score variation between pre- and post-treatment (day 21) samples. CelTIL combines % of tumor cellularity and % of tumor-infiltrating lymphocytes into a single score. DNA and RNA were purified from pre-treatment baseline FFPE tumor samples. Gene expression was evaluated using a custom 67-gene panel on the nCounter. NGS-based DNA-seq was performed using the VHIO-300 panel, which estimates tumor mutational burden (TMB), identifies copy-number aberrations (CNAs) across the entire genome and calls mutational status of >300 genes. From CNA data, 150 previously defined DNA-based signatures (Xia et al. Nat Comm 2019) trained to capture RNA- and protein-based phenotypes such as the PAM50-related biology were evaluated. Associations of each variable with efficacy (i.e., CelTIL relative changes, and tumor cellularity relative changes) were adjusted for multiple-testing (false discovery rate [FDR] < 5%). The area under the ROC Curve (AUC) was used to estimate the discrimination performance of each variable. Results: RNA and DNA data were obtained from 45 (58%) patients. Baseline characteristics in this subset of patients were generally similar to the original TOT-HER3 population. Among 228 variables (single mutation status, single gene expression, PAM50 signatures, TMB, and DNA CNA-based signatures), 139 (61%) were found significantly associated (FDR< 5%) with CelTIL changes at day 21. Among them, TP53 mutations (n=7) were found associated with higher CelTIL response compared to TP53 wild type (71% [95% CI=-5.4-17.8] vs. 24% [95% CI=15.9-55.4], FDR=2.1%). In addition, RNA-based genes tracking Basal-related biology (e.g., CCNE1, AUC=0.71) or immune expression (e.g., PDCD1, AUC=0.73, or CD68, AUC=0.62), together with RNA/DNA-based signatures tracking proliferation and/or basal-related biology (e.g., retinoblastoma loss-of-heterozygozity [RB-LOH], AUC=0.76), were associated with high CelTIL response. Conversely, RNA/DNA-based signatures tracking endocrine sensitivity/Luminal A-related biology (e.g., Scorr_IE_Correlation, AUC=0.76) were associated with low/lack of CelTIL response. PIK3CA somatic mutations (n=14, 31% of cases), and TMB (range 2.2-12.7) were not found associated with CelTIL response. Similar overall results were obtained when relative changes in tumor cellularity (instead of CelTIL) was evaluated as the efficacy endpoint. Conclusions: TP53 mutations, immune-related genes, and DNA/RNA-based phenotypic signatures tracking Basal- or Luminal A-related biology such as the DNA-based RB-LOH score or the endocrine sensitivity score (Scorr_IE_Correlation) are associated with CelTIL changes in response to HER3-DXd in HR+/HER2- breast cancer. Further RNA- and DNA-based analyses will be evaluated. Citation Format: Fara Brasó-Maristany, Claudette Falato, Olga Martínez-Sáez, Juan Miguel Cejalvo, Mireia Margelí, Pablo Tolosa, Francisco Javier Salvador Bofill, Josefina Cruz, Blanca González-Farré, Esther Sanfeliu, Míriam Arumí, Guillermo Villacampa, Eva Ciruelos, Martín Espinosa-Bravo, Yann Izarzuzaga, Patricia Galván, Judit Matito, Sonia Pernas, Anu Santhanagopal, Stephen Esker, Parul Patel, Pang-Dian Fan, Juan Manuel Ferrero-Cafiero, Ana Vivancos, Tomás Pascual, Aleix Prat, Mafalda Oliveira. Genetic determinants of response to patritumab deruxtecan (HER3-DXd) in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer: a correlative analysis from SOLTI TOT-HER3 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-31.

The 7th generation Jacinto™ SoC platform is an evolution of prior architectures [1], [2] and integrates new capabilities to support a wide set of applications, including automotive, industrial, and broad market. This drives a diverse set of requirements which need IP innovation and new techniques across the entire SoC stack including: high-reliability techniques for automotive, including circuit analysis and screening; new IP development including new DSP, signal processing and data movement architectures; embedded vision, machine learning, and imaging and video acceleration; new security and safety innovations, including an integrated safety MCU; dedicated security controller, and hardware features to enable ASIL-D support. This SoC platform and first implementation also integrates techniques for simplified power-supply management and support for cost-sensitive systems through on-die micro-architecture solutions.

Introduction: The swellings of foot are common but the lesions of metatarsals are rare. The purpose is to highlight these four cases which had almost common presentations but had different etiologies. Case Report: A series of four cases all of which had similar presentation, but different etiologies. One case had foreign body (FB) granuloma, one had tibialis anterior (TA) tendinosis and the other two cases had osteomyelitis, one pyogenic and the other tubercular. All cases underwent curettage and removal of the pathogenic foci, and were diagnosed with tissue biopsies. Conclusion: Clinical signs in tuberculous (TB) osteomyelitis, pyogenic osteomyelitis, FB granuloma, and tendinosis are generally subtle and lead in most cases to a late diagnosis. In developing countries, where most of the people walk barefoot, FB granuloma due to thorn prick should always be considered as a differential diagnosis. Although rare to find tendinosis of TA, TB osteomyelitis, pyogenic osteomyelitis, and FB granuloma of metatarsals, these conditions should always be considered as differential diagnosis along with tumors.

Background: There is an alarmingly high prevalence of hypovitaminosis D in orthopaedic patients, regardless of whether or not, they require surgical intervention. Vitamin D plays an essential role in bone formation, maintenance, and remodelling, as well as muscle function and deficiency could affect adversely in multiple ways. Many reports recently demonstrated high rates of vitamin D deficiency, in numerous segments of Indian population, but there is no study reported so far from India, which focuses specifically on vitamin D status in orthopaedic patients.Methods: It is a descriptive study to estimate vitamin D levels in patients scheduled to undergo orthopaedic surgery. Vitamin D, calcium, phosphorus and alkaline phosphatase (ALP) levels in 310 patients, who were admitted at our institution, from December 2015 to August 2017 were measured.Results: Out of 310 patients included in our study, 189 (61%) were males and 121 (39%) females. Vitamin D deficiency (30 ng/ml). Patients younger than 60 years and males had more prevalence of Vitamin D abnormality. 168 (72.4%) of the patients, with deficiency presented in winter, compared to 64 (27.6%) in summer.Conclusions: Statistically significant vitamin D deficiency was seen during winter months, in patients undergoing hip hemiarthroplasty, and in patients admitted for degenerative disease of the spine, hip and knee. Screening and treating hypovitaminosis D appears to be important in orthopaedic patients as vitamin D deficiency is prevalent across all age groups in the population studied.

This work is part of the TIRAMISU project, funded by the European Commission’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n◦284747 and the Engineering and Physical Sciences Research Council (EPSRC) grants EP/J009016/1 and EP/F059922/1. I.D.W.S. and P.J.S. are Royal Society Wolfson Research Merit Award holders. The density of organic semiconductor films is an important quantity because it is related to intermolecular spacing which in turn determines the electronic and photophysical properties. We report thin film density and refractive index measurements of polyfluorenes and star-shaped oligofluorene truxene molecules. An ellipsometer and a procedure using a spectrophotometer were used to determine film thickness and mass of spin-coated films, respectively. We present a study of the effect of alkyl side-chain length on the volumetric mass density and refractive index of the materials studied. The density measured for poly(9,9-di-n-octylfluorene) (PF8) was 0.88 ± 0.04 g/cm3 and decreased with longer alkyl side chains. For the truxene molecule with butyl side chains (T3 butyl), we measured a density of 0.90 ± 0.04 g/cm3, which also decreased with increasing side-chain length. Postprint

Background and objective: Bisphosphonates are commonly used to treat and prevent osteoporosis. These compounds have unusual pharmacokinetic characteristics because they bind strongly to bone, and a portion becomes buried under newly formed bone. Once incorporated into bone tissue, the subsequent release during bone remodeling is probably the rate-limiting step in the terminal elimination of bisphosphonates. Because of this unique property of bisphosphonates, pharmacokinetic studies with insufficient lengths of follow-up might entirely miss the true terminal elimination phase. A terminal half-life (t1/2γ) of approximately 11 years, similar to that of calcium and other minerals in bone, was reported from an 18-month study of alendronic acid in postmenopausal women with osteoporosis. We are not aware of any other published reports in which the elimination of a bisphosphonate has been followed for more than a few weeks post-dose. The purpose of the present study was to reanalyse the alendronic acid data to examine the effect of truncating the length of follow-up on the calculated t1/2γ. Patients and methods: Twenty-one postmenopausal women with osteoporosis (mean age 66 years) received intravenous alendronic acid 30mg over 4 consecutive days (7.5 mg/day), and urinary excretion of alendronic acid was monitored over the following 18–24 months. Terminal elimination half-life was originally calculated by log-linear regression of the percentage retained versus time curve between days 240 and 540 and substituting the slope of the regression line into the equation, t1/2γ = −log 2/slope. These data were reanalysed based on the period up to 30 days. Results: Data were sufficient for analysis of pharmacokinetics in 11 patients. A mean t1/2γ of approximately 11 years was reported previously, based on analysis of data between days 240 and 540. Recalculating the ‘terminal’ half-life of alendronic acid using only data from the first 30 days resulted in an ‘observed’ half-life of only 11 days. Conclusion: This analysis illustrates the importance of sufficient length of follow-up to accurately characterise the true terminal elimination half-life of bisphosphonates. The relatively short (expressed in units of days rather than years) terminal elimination half-lives reported for some bisphosphonates based on only 30 days of follow-up or less are likely to substantially underestimate the true terminal elimination half-lives.

Insulin-like growth factor I (IGF-I) is thought to stimulate bone resorption indirectly through a primary effect on osteoblasts, which in turn activate osteoclasts by as-yet-unidentified mechanisms. Small decreases in extracellular pH (pHo) dramatically increase the resorptive activity of osteoclasts. Our purpose was to characterize the effect of IGF-I on acid production by osteoblastic cells. When confluent, UMR-106 osteoblast-like cells and rat calvarial cells acidified the compartment beneath them. Superfusion with IGF-I caused a further decrease in pHo. To investigate the mechanism, we monitored acid efflux from subconfluent cultures. IGF-I rapidly increased net efflux of H+ equivalents in a concentration-dependent manner. IGF-II (10 nM) evoked a smaller response than IGF-I (10 nM). The response to IGF-I was partially dependent on extracellular Na+, but not glucose, and exhibited little if any desensitization. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, abolished the response to IGF-I but not to parathyroid hormone. Thus IGF-I enhances acid efflux from osteoblastic cells, via a signaling pathway dependent on activation of phosphatidylinositol 3-kinase. In vivo, acidification of the compartment between the osteogenic cell layer and the bone matrix may affect diverse processes, including mineralization and osteoclastic bone resorption.

While it is well established that adenylyl cyclase and phospholipase C-β are two proximal signal effectors for the calcitonin receptor, the more distal signaling pathways are less well characterized. G protein-coupled receptors can activate Erk1/2 by Gs-, Gi-, or Gq-dependent signaling pathways, depending on the specific receptor and cell type examined. Since the calcitonin receptor can couple to all three of these G proteins, the ability of calcitonin to activate Erk1/2 was investigated. Calcitonin induced time- and concentration-dependent increases in Shc tyrosine phosphorylation, Shc-Grb2 association and Erk1/2 phosphorylation and activation in a HEK 293 cell line that stably expresses the rabbit calcitonin receptor C1a isoform. Pertussis toxin, which inactivates Gi, and calphostin C, a protein kinase C inhibitor, each partially inhibited calcitonin-induced Shc tyrosine phosphorylation, Shc-Grb2 association, and Erk1/2 phosphorylation. In contrast, neither forskolin nor H89, a protein kinase A inhibitor, had a significant effect on basal or calcitonin-stimulated Erk1/2 phosphorylation. Our results suggest that the calcitonin receptor induces Shc phosphorylation and Erk1/2 activation in HEK293 cells by parallel Gi- and PKC-dependent mechanisms. The calcitonin-induced elevation of cytosolic free Ca2+ was required for Erk1/2 phosphorylation, since preventing any change in cytosolic free Ca2+ by chelating both cytosolic and extracellular Ca2+ abolished the response. However, the change in Ca2+ that is induced by calcitonin is not sufficient to account for the calcitonin-induced Erk1/2 phosphorylation, since treatment with 100 nm ionomycin or 10 μm thapsigargin, each of which induced elevations of Ca2+ comparable to those induced by calcitonin, induced significantly less Erk1/2 phosphorylation than that induced by calcitonin. Erk1/2 may have important roles as downstream effectors mediating cellular responses to calcitonin stimulation.

Three oxo-bridged diiron(III) complexes of L-histidine and heterocyclic bases [Fe-2(mu-O)(L-his)(2)(B)(2)](ClO4)(2) (1-3), where B is 2,2'-bipyridine (bpy),1,10-phenanthroline (phen), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), were prepared and characterized. The bpy complex 1 was structurally characterized by X-ray crystallography. The molecular structure showed a {Fe-2(mu-O)} core in which iron(III) in a FeN4O2 coordination is bound to tridentate monoanionic L-histidine and bidentate bpy ligands. The Fe center dot center dot center dot Fe distance is similar to 3.5 angstrom. The Fe-O-Fe unit is essentially linear, giving a bond angle of similar to 172 degrees. The complexes showed irreversible cyclic voltammetric cathodic response near -0.1 V vs. SCE in H2O-0.1 M KCl. The binuclear units displayed antiferromagnetic interaction between two high-spin (S = 5/2) iron(III) centers giving a -J value of -110 cm(-1). The complexes showed good DNA binding propensity giving a binding constant value of similar to 10(5) M-1. Isothermal titration calorimetric data indicated single binding mode to the DNA. The binding was found to be driven by negative free energy change and enthalpy. The dpq complex 3 showed oxidative double-strand DNA cleavage on exposure to UV-A and visible light. The phen complex 2 displayed single-strand photocleavage of DNA. The DNA double-strand breaks were rationalized from theoretical molecular docking calculations. Mechanistic investigations showed formation of hydroxyl radicals as the reactive species through photodecarboxylation of the L-histidine ligand. The complexes exhibited good binding propensity to bovine serum albumin (BSA) protein in Tris-HCl/NaCl buffer medium. The dpq complex 3 showed UV-A light-induced site-specific oxidative BSA cleavage forming fragments of similar to 45 kDa and similar to 20 kDa molecular weights via SOH pathway.

Four (mu-oxo)diiron(iii) complexes [Fe(2)(mu-O)(H(2)O)(2)B(4)](ClO(4))(4) ( and ) and [Fe(2)(mu-O)(mu-O(2)CMe)B(4)](ClO(4))(3) ( and ), where B = 1,10-phenanthroline (phen) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), are prepared and their DNA binding and cleavage activity studied. The complexes show DNA binding propensity giving K(b) values of 3.6-9.3 x 10(4) M(-1). The viscosity and DNA melting data suggest a surface and/or groove binding nature of the complexes to calf thymus (CT) DNA. The DNA binding data obtained from isothermal calorimetric study indicate two binding modes involving surface aggregation and/or partial intercalation of the phenanthroline bases to CT DNA. All the complexes show chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent following a mechanistic pathway that involves formation of superoxide and hydroxyl radicals. Photoirradiation of pUC19 DNA at 365 nm in the presence of 1-4 show that the complexes, barring 1 , are efficient photocleavers of supercoiled DNA to its nicked circular form. Complexes 2-4 display photocleavage activity in visible light of different wavelengths. Complexes 3 and 4 exhibit significant DNA cleavage activity in red light of 633 nm, the wavelength known for the activity of the photodynamic therapeutic drug Photofrin. The mechanistic study using various additives suggests a minor groove binding nature of the complexes with the formation of singlet oxygen from the quinoxaline moiety of dpq and hydroxyl radical from photodecarboxylation of the acetate ligand as the reactive oxygen species.

A 15-yr old boy presented with low backache for 4 months associated with weakness of left lower limb. MRI of lumbosacral spine showed a sacral lesion with intraspinal and presacral soft tissue extension with neural compression. A diagnosis of tuberculosis was considered in the view of high prevalence in this part of the world, however biopsy revealed Ewing's sarcoma. Ewing's tumor of sacrum is rare, but should be suspected in low backache in children. Differential diagnosis for a sacral lesion includes tuberculosis, pyogenic osteomyelitis, lymphoma, chordoma, osteosarcoma and Ewing's sarcoma. MRI is sensitive in detecting these lesions but is nonspecific requiring histopathological examination for confirmation.

Sebaceous horns (de la Pena Zarzuelo et al., Arch Esp Urol 54:367-368, 2001; Vera-Donoso, Scand J Urol Nephrol 43:92-93, 2009) are rare on the penis, as they are commonly seen only on sun-exposed areas. A 45-year-old male presenting with multiple sebaceous horns of the penis is reported here. Excision of the horn with a rim of normal tissue in the base was done. Histopathological examination revealed no malignant change.

Proton efflux from chondrocytes alters the extracellular pH and ionic composition of cartilage, and influences the synthesis and degradation of extracellular matrix. Epidermal growth factor (EGF) promotes chondrocyte proliferation during skeletal development and accumulates in the synovial fluid in rheumatoid arthritis. The purpose of this study was to investigate the effect of EGF on proton efflux from chondrocytes. When monitored using a Cytosensor microphysiometer, EGF was found to rapidly activate proton efflux from CFK2 chondrocytic cells and rat articular chondrocytes. The actions of EGF were concentration-dependent with half-maximal effects at 0.3-0.7 ng/ml. Partial desensitization and time-dependent recovery of the response were observed following repeated exposures to EGF. EGF-induced proton efflux was dependent on extracellular glucose, and inhibitors of Na + /H + exchange (NHE) markedly attenuated the initial increase in proton efflux. The response was diminished by inhibitors of phosphatidylinositol 3-kinase and phospholipase C, but not by inhibitors of MEK (MAPK/ERK kinase) or protein kinase A or C. Thus, EGF-induced proton efflux involves glucose metabolism and NHE, and is regulated by a discrete subset of EGF-activated signaling pathways. In vivo, proton efflux induced by EGF may lead to an acidic environment, enhancing turnover of cartilage matrix during development and in rheumatoid arthritis. J. Cell. Physiol. 192: 102-112, 2002. E 2002 Wiley-Liss, Inc.

Two isoforms of the calcitonin receptor are expressed in rabbit: the common C1a isoform and the calcitonin receptor Delta e13 isoform, which has a deletion in the seventh transmembrane domain. Using microphysiometry, we investigated the effects of calcitonin on proton efflux from HEK293 cells stably transfected with C1a, calcitonin receptor Delta e13, or empty vector. In C1a-expressing cells only, calcitonin rapidly induced a biphasic elevation in proton efflux consisting of an initial transient and a sustained plateau, accompanied by an increase in lactate efflux. Inhibitors of Na(+)/H(+) exchange abolished only the initial transient, whereas removal of extracellular glucose abolished only the sustained plateau. These data suggest that activation of Na(+)/H(+) exchange mediates the initial transient, whereas increased glucose metabolism underlies the sustained plateau. Because both receptor isoforms activate adenylyl cyclase, the lack of effect of calcitonin on proton efflux from calcitonin receptor Delta e13-expressing cells argued against involvement of cAMP in activating proton efflux. Similarly, studies involving elevation or buffering of cytosolic free Ca(2+) concentration argued against involvement of Ca(2+). Activation of PKC mimicked the plateau phase of calcitonin-induced proton efflux from C1a cells, whereas inhibition or depletion of PKC suppressed it. Activation of proton transport and production are novel cellular responses to calcitonin, mediated selectively by the C1a receptor isoform via a mechanism involving PKC.

While it is well established that adenylyl cyclase and phospholipase C-beta are two proximal signal effectors for the calcitonin receptor, the more distal signaling pathways are less well characterized. G protein-coupled receptors can activate Erk1/2 by Gs-, Gi-, or Gq-dependent signaling pathways, depending on the specific receptor and cell type examined. Since the calcitonin receptor can couple to all three of these G proteins, the ability of calcitonin to activate Erk1/2 was investigated. Calcitonin induced time- and concentration-dependent increases in Shc tyrosine phosphorylation, Shc-Grb2 association and Erk1/2 phosphorylation and activation in a HEK 293 cell line that stably expresses the rabbit calcitonin receptor C1a isoform. Pertussis toxin, which inactivates Gi, and calphostin C, a protein kinase C inhibitor, each partially inhibited calcitonin-induced Shc tyrosine phosphorylation, Shc-Grb2 association, and Erk1/2 phosphorylation. In contrast, neither forskolin nor H89, a protein kinase A inhibitor, had a significant effect on basal or calcitonin-stimulated Erk1/2 phosphorylation. Our results suggest that the calcitonin receptor induces Shc phosphorylation and Erk1/2 activation in HEK293 cells by parallel Gi- and PKC-dependent mechanisms. The calcitonin-induced elevation of cytosolic free Ca2+ was required for Erk1/2 phosphorylation, since preventing any change in cytosolic free Ca2+ by chelating both cytosolic and extracellular Ca2+ abolished the response. However, the change in Ca2+ that is induced by calcitonin is not sufficient to account for the calcitonin-induced Erk1/2 phosphorylation, since treatment with 100 nM ionomycin or 10 microM thapsigargin, each of which induced elevations of Ca2+ comparable to those induced by calcitonin, induced significantly less Erk1/2 phosphorylation than that induced by calcitonin. Erk1/2 may have important roles as downstream effectors mediating cellular responses to calcitonin stimulation.