Bone Organ Research Articles

An Autophagy-Targeting Chimera Induces Degradation of Androgen Receptor Mutants and AR-v7 in Castration-Resistant Prostate Cancer.

Genetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer (PCa) progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in PCa and co-degrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive PCa cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.

Humanized In Vivo Bone Tissue Engineering: In Vitro Preculture Conditions Control the Structural, Cellular, and Matrix Composition of Humanized Bone Organs.

Bone tissue engineering (BTE) has long sought to elucidate the key factors controlling human/humanized bone formation for regenerative medicine and disease modeling applications, yet with no definitive answers due to the high number and co-dependency of parameters. This study aims to clarify the relative impacts of in vitro biomimetic 'preculture composition' and 'preculture duration' before in vivo implantation as key criteria for the optimization of BTE design. These parameters are directly related to in vitro osteogenic differentiation (OD) and mineralization and are being investigated across different osteoprogenitor-loaded biomaterials, specifically fibrous calcium phosphate-polycaprolactone (CaP-mPCL) scaffolds and gelatin methacryloyl (GelMA) hydrogels. The results show that OD and mineralization levels prior to implantation, enhanced by a mineralization medium supplement to the osteogenic medium (OM), significantly improve ectopic BTE outcomes, regardless of the biomaterial type. Specifically, preculture conditions are pivotal in achieving more faithful mimicry of human bone structure, cellular and extracellular matrix composition and organization, and provide control over bone marrow composition. This work emphasizes the potential of using biomimetic culture compositions, specifically the addition of a mineralization medium as a cost-effective and straightforward approach to enhance BTE outcomes, facilitating rapid development of bone models with superior quality and resemblance to native bone.

Isolated Langerhans Cell Histiocytosis of the Thyroid: A very rare case report

Langerhans cell histiocytosis (LCH) is a group of diseases that cause damage by local or widespread accumulation of atypical histiocytes in various tissues such as skin, bone, lung, liver, lymph nodes, mucocutaneous tissues, and endocrine organs. LCH was detected as a result of a total thyroidectomy biopsy performed on a 43-year-old female patient with a solitary euthyroid nodule following weight loss and an increase in the size of the thyroid nodule during outpatient clinic checks. Patient's whole body positron emission tomography. The case of LCH with isolated thyroid involvement is very rare, and a limited number of cases have been presented on this subject. In addition, it will contribute to the literature since there are fewer than ten LCH cases with thyroid involvement.

Inferring the metabolic rate of bone

The bone organ is poorly represented in comparative research on mammalian mass-specific metabolic rates. As a first order attempt to remedy this, from the literature we collected mass-specific metabolic rates for all major organs except for the bone organ, and by subtraction infer the rate for the bone organ. The scaling relationships are given of each whole-organ mass-specific metabolic rate and of the relationship between whole-organ metabolic rate and body mass. Scaling of the lung, adipose depot and bone organ with body mass is higher than would be expected by ¾ power scaling. We interpret the similar scalings of bone and the adipose depot in light of their evolved regulation of whole-body metabolism. We also briefly examine the supra-¾ power scaling of the lung as well as the independence of the mass-specific metabolic rate of the heart from body mass. The bone organ exhibits relatively high energy expenditure with increasing body size. The bone marrow and its medullary adipocyte store may be responsible for engendering the greater share of the bone organ's energetic cost.

Radioecological characteristics of Siberian roe deer (Capreolus pygargus Pal., 1771) inhabiting locations of nuclear weapon tests.

This paper reports the activity concentrations of 137Cs, 90Sr, 239+240Pu, 241Am, and 3Н in the form of tritiated water (НТО) and organically bound tritium (ОBТ) in the tissues and organs of roe deer (Capreolus pygargus Pal., 1771) that inhabit the 'Degelen' test location of the Semipalatinsk Test Site. Tissues and organs were sampled from six deer by killing. The activity concentrations of specific radionuclides in the samples were measured using γ-, α-, and β-spectrometry. The radionuclide activity concentrations in the tissues and organs showed considerable variation, for example, 0.6-170 Bq kg-1 for 137Cs and 0.3-2.8×103 Bq kg-1 for 90Sr. The activity concentrations of radionuclides in animal muscular tissue did not exceed permissible values for the meat of wild animals. The tissues and organs in the roe deer were arranged as follows in descending order of their ability to accumulate 137Cs and 90Sr: for 137Cs, muscular tissue-kidneys-lungs-spleen-heart-liver-bone tissue; for 90Sr, bone tissue-liver-lungs-muscular tissue-spleen-heart-kidneys. The activity concentrations of 241Am and 239+240Pu did not exceed the minimum detectable activity. Therefore, no quantitative values could be determined for 241Am, and the 239+240Pu activity concentration could be derived for only one sample: 0.5±0.1 Bq kg-1 (liver). The distribution pattern of these radionuclides in the tissues and organs of the roe deer could not be determined because of insufficient data. The HTO volumetric activity in the tissues and organs of the examined animals ranged from 2.6×10-2 to 77 kBq l-1; activity concentration of OBT, 3.0×10-2 to 16 kBq kg-1; and OBT-to-HTO ratios, 2.0×10-3 to 5.3×102. This ratio can serve as an indicator of how long the examined animals stay in radioactively contaminated ecosystems. Within the 'Degelen' site, the activity concentrations of 90Sr and tritium, in the form of HTO and OBT, are expected to be high in the bone tissues, soft tissues, and organs, respectively.

Global hotspots and research trends of radiation-induced skin injury: a bibliometric analysis from 2004 to 2023.

Radiation therapy has become an important treatment for many malignant tumours after surgery and for palliative tumour care. Although modern radiotherapy technology is constantly improving, radiation damage to normal tissues is often difficult to avoid, and radiation-induced skin injury (RSI) is a common complication, manifested as skin erythema, peeling, ulceration, and even bone and deep organ damage, seriously affect the quality of life for patients. Basic research and clinical trials related to RSI have achieved certain results, while no researchers have conducted comprehensive bibliometric studies. A comprehensive bibliometric analysis of publications on RSI published between 2004 and 2023 was conducted to identify current hotspots and future directions in this area of study. RSI-related publications published between January 1, 2004, and December 31, 2023, were retrieved from the Web of Science Core Collection (WoSCC) database for analysis using VOSviewer and CiteSpace analytics. A total of 1009 publications on RSI from 2004 to 2023 were included in the WoSCC database. The United States had the highest productivity with 299 papers, accounting for 29.63% of the total production, followed by China with 193 papers (19.13%) and Japan with 111 papers (11.00%). In terms of research institutions and journals, the University of Toronto and Journal of Supportive Care in Cancer published the highest number of papers. Professor Edward Chow published the most articles, while Professor Shuyu Zhang was the most cited. The top ten most-cited papers focused on the pathogenesis, prevention, and management of RSI. Keyword co-occurrence analysis and the top 25 keywords with the strongest citation bursts suggest that current research focuses on the pathogenesis, prevention, and treatment management of RSI. This study conducted a systematic bibliometric analysis of RSI publications from 2004 to 2023; identified the trends in RSI publications, major research countries, major research institutions, major research journals, major research authors, and major research keywords; and revealed the future development direction and research hotspots of this field. This study provides a valuable reference for future RSI research.

Characteristics and radiological hazard assessment of 210Po in tilapia (Oreochromis niloticus) in Vietnam.

210Po is one of the most toxic natural radionuclides. This isotope's characteristics and radiological hazard assessment have been concerned in different objects. In this study, the 210Po activities were determined in different tilapia organs/parts of 20 sample groups by alpha spectrometry. The 210Po activities in muscle, bone, intestine organs, and stomach contents unevenly distributed with a wide range from 0.5 ± 0.2 to 2.8 ± 0.4 and 1.4 ± 0.2Bq·kg-1 wet.wt on average, from 0.6 ± 0.3 to 6.3 ± 0.7 and 3.5 ± 0.4Bq·kg-1 wet.wt on average, from 46.3 ± 2.9 to 263 ± 9.7 and 115 ± 6Bq·kg-1 wet.wt on average, and 20.9 ± 1.2 to 800 ± 29 and 197 ± 9Bq·kg-1 wet.wt on average, respectively. The average 210Po activities in different parts of tilapia trend in order of CMuscle < CBone < CIntestine < CStomach contents. Insignificant correlations were observed between 210Po activities in tilapia organs with their total fish mass. The result could depend on feeding types, diet, different nutrient levels, metabolism, and excretion of 210Po in different ages. The concentration ratios (CRs) of tilapia muscle and bone organs were recorded with low values, while it was far greater than the CRs for the intestine organ. Annual committed effective doses contributing from 210Po concentration due to tilapia fish consumption were within the allowable limits for muscle and bone organs, while those values for intestine organs were far higher than the allowable limit value (assuming similar amount consumption of 30kg·year-1 for each organ). The Erica tool was used to estimate the dose and risk to tilapia from 210Po exposure. Based on the calculated results, it can be seen that there was insignificant concern for tilapia due to ionizing radiation in the study area.

Cutibacterium acnes invades submicron osteocyte lacuno-canalicular networks following implant-associated osteomyelitis.

Cutibacterium acnes, part of normal skin flora, is increasingly recognized as an opportunistic pathogen capable of causing chronic prosthetic joint infections (PJI) associated with total hip and knee arthroplasty. However, there is a paucity of literature examining the pathogenesis of C. acnes during PJI. To study this, we developed an implant-associated osteomyelitis murine model in which 8-10-week-old C57BL6 mice were subjected to transtibial implantation of titanium or stainless-steel L-shaped pins contaminated with C. acnes. Postsurgery, mice were killed on Days 14 and 28 for terminal assessments of (1) bacterial load in bone, implant, and internal organs (heart, spleen, kidney, and liver), (2) bone osteolysis (micro-CT), (3) abscess formation (histology), and (4) systematic electron microscopy (EM). In vitro scanning EM (SEM) confirmed that C. acnes can form biofilms on stainless-steel and titanium implants. In mice, C. acnes could persist for 28 days in the tibia. Also, we observed C. acnes dissemination to internal organs. C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation compared to Staphylococcus aureus infections. Importantly, transmission EM (TEM) investigation revealed the presence of C. acnes within canaliculi, demonstrating that C. acnes can invade the osteocyte lacuno-canalicular networks (OLCN) within bone. Our preliminary pilot study, for the first time, revealed that the OLCN in bone can be a reservoir for C. acnes and potentially provides a novel mechanism of why C. acnes chronic implant-associated bone infections are difficult to treat.

Human post-implantation blastocyst-like characteristics of Muse cells isolated from human umbilical cord

Muse cells, identified as cells positive for the pluripotent surface marker SSEA-3, are pluripotent-like endogenous stem cells located in the bone marrow (BM), peripheral blood, and organ connective tissues. The detailed characteristics of SSEA-3(+) cells in extraembryonic tissue, however, are unknown. Here, we demonstrated that similar to human-adult tissue-Muse cells collected from the BM, adipose tissue, and dermis as SSEA-3(+), human-umbilical cord (UC)-SSEA-3(+) cells express pluripotency markers, differentiate into triploblastic-lineage cells at a single cell level, migrate to damaged tissue, and exhibit low telomerase activity and non-tumorigenicity. Notably, ~ 20% of human-UC-SSEA-3(+) cells were negative for X-inactive specific transcript (XIST), a naïve pluripotent stem cell characteristic, whereas all human adult tissue-Muse cells are XIST-positive. Single-cell RNA sequencing revealed that the gene expression profile of human-UC-SSEA-3(+) cells was more similar to that of human post-implantation blastocysts than human-adult tissue-Muse cells. The DNA methylation level showed the same trend, and notably, the methylation levels in genes particularly related to differentiation were lower in human-UC-SSEA-3(+) cells than in human-adult tissue-Muse cells. Furthermore, human-UC-SSEA-3(+) cells newly express markers specific to extraembryonic-, germline-, and hematopoietic-lineages after differentiation induction in vitro whereas human-adult tissue-Muse cells respond only partially to the induction. Among various stem/progenitor cells in living bodies, those that exhibit properties similar to post-implantation blastocysts in a naïve state have not yet been found in humans. Easily accessible human-UC-SSEA-3(+) cells may be a valuable tool for studying early-stage human development and human reproductive medicine.

Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.

The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.

Neoadjuvant chemo-immunotherapy following concurrent immuno-chemoradiotherapy and immune-maintenance therapy as primary treatment for locally advanced cervical cancer: A prospective, single-arm, phase 2 trial.

5533 Background: Immunotherapy in combination with chemoradiotherapy has shown good efficacy in locally advanced cervical cancer (LACC). We report on the efficacy of neoadjuvant camrelizumab plus chemotherapy (TP) following concurrent immuno-chemoradiotherapy and maintenance immunotherapy for LACC. Methods: Eligible participants were adults with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2018 stage IIB-IVA disease), ECOG PS score 0-2, and adequate bone marrow and organ function. All pts received 2 cycles neoadjuvant camrelizumab (200 mg d1 q3w) plus TP (albumin-bound Paclitaxel 260mg/m2 d1 q3w; cisplatin 75 mg/m2 d1-3 q3w) treatment, following 5-week external beam radiotherapy (EBRT) protocol (45-50 Gy/25 fractions with concurrent triweekly camrelizumab and cisplatin) to the whole pelvis plus brachytherapy every 3 weeks for 2 cycles, and then maintenance therapy of camrelizumab (200mg q3w, up to one year). The primary endpoint was progression-free survival (PFS) at 2 years. PFS was evaluated when at least 13 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.05. Results: 67 pts provided informed consent and 12 were excluded for not meeting eligibility. 55 pts received the investigational agent and were evaluable for safety and efficacy analyses. The median age was 54 years [IQR 50 to 60]; 51 [92.7%] were squamous cell carcinoma, and 4 [7.3%] were adenocarcinoma; 9 [16.4%] were stage IIB, 2 [3.6%] were IIIA, 5 [9.1%] were IIIB, 30 [54.5%] were IIIC1r, 6 [10.9%] were IIIC2r, and 3 [5.5%] were IVA. As of data cutoff (Jan. 15, 2024), median follow-up was 9.5 (IQR 7.1 to 10.3) months. Of the 55 pts, 1 (1.8%) pt underwent hysterectomy after EBRT because of pelvic empyema, and was excluded from response evaluation. At three months after brachytherapy, the overall remission rate was 100% (53 [98.1%] complete remission and 1 [1.9%] partial remission). We identified 3 (5.5%) pts with treatment failure (2 [3.6] distant metastasis, and 1 [(1.8%] para-aortic lymph node relapse) during follow-up; 1-year PFS was 90.6% (85.4%-95.8%). The most common clinically significant grade 3-4 adverse events (AEs) were decreased neutrophils (18.2%), thrombocytopenia (9.1%) and anemia (27.3%). Serious AEs occurred in 7 (12.7%), most commonly due to infectious complications. There were no treatment-related deaths. Conclusions: The interim data support Camrelizumab plus TP neoadjuvant chemo-immunotherapy following immuno-chemoradiotherapy and Camrelizumab maintenance therapy as an active go-forward regimen in LACC. No new safety signals were observed, and most AEs were mild to moderate. Clinical trial information: ChiCTR2200061097.

Abstract PO2-05-04: ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC)

Abstract Background: ER+/HER2- breast cancer (BC) is the most prevalent BC subtype. Endocrine therapy (ET) is the mainstay of treatment; however, development of resistance to this therapeutic approach is common in the metastatic setting. After progression on first-line treatment, both ET monotherapy and combination therapy options are available. Combinations such as everolimus + exemestane and alpelisib + fulvestrant can be associated with higher efficacy, but also significant toxicity with discontinuation rates around 25%. Also, for second-line treatment, pts who did not receive prior treatment with a CDK4/6i, the combination of fulvestrant with a CDK4/6i (palbociclib, abemaciclib, and ribociclib) are among the recommended treatment options for this pt population (NCCN, 2022). However, fulvestrant has low bioavailability and an IM injection burden. The crosstalk between the three pathways ER, PI3K/AKT/mTOR and cyclin-dependent kinases (CDK4/6) provide a rationale for the combination of elacestrant, a next-generation oral SERD, with inhibitors of these pathways that are natural targets to overcome endocrine resistance. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC ET in pts with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following disease progression on prior ET (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. The replacement of the fulvestrant backbone with elacestrant in combination with targeted agents enabling oral-oral combinations is of therapeutic interest. Methods: ELEVATE (NCT05563220) is a phase 1b/2 clinical trial that will evaluate the safety and efficacy of elacestrant combined with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. Eligible pts must be adults with confirmed ER+/HER2− advanced or mBC, &amp;gt; 1 measurable lesion as per RECIST v1.1, and adequate bone marrow or organ function. The main objectives for Phase 1b are to determine the RP2D of elacestrant combined with other targeted agents. The RP2D of elacestrant and abemaciclib will be determined in the ELECTRA study (NCT05386108). The Phase 2 portion will evaluate the efficacy of elacestrant combined with other study drugs for PFS; secondary objectives include PK of the various combinations, ORR, DoR, CBR, PFS, and OS. Here we report the initial dosing from the Phase 1b portion. Results: As of June 2023, 11 pts were enrolled in the phase 1b portion of the trial, cohort 1 for all combinations: 5 pts in the elacestrant and everolimus (300 mg elacestrant QD/everolimus 5 mg QD) and 3 pts in the elacestrant and alpelisib (300 mg elacestrant QD/alpelisib 250 mg QD) and 2 patients for palbociclib and 1 patient in the ribociclib combinations. Further patient accrual is expected in phase 1b cohorts of various combinations during the second half of 2023; both safety and PK data will be provided. Conclusion: In the Phase 1b portion of ELEVATE, elacestrant is being combined with various targeted agents enabling oral-oral combinations to determine a RP2D. Recruitment is actively ongoing; safety and PK results will be presented at the meeting from the completed phase 1b cohorts. Citation Format: Hope Rugo, Aditya Bardia, Javier Cortés, Giuseppe Curigliano, Erika Hamilton, Sara Hurvitz, Sibylle Loibl, Sara Tolaney, Virginia Kaklamani, Giulia Tonini, Shannon Matheny, Kathy Puvana Theall, Joyce O'Shaughnessy. ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-04.

Bone Mechanical Loading Reduces Heart Rate and Increases Heart Rate Variability via the Autonomic Nervous System in Anesthetized Mice

Mechanical loading of bone creates interstitial fluid flow and shear stress within the bone lacunocanalicular system, leading to alterations of bone size and mass. Bone plays an important role as an endocrine organ, releasing endocrine signaling molecules that impact systemic physiology. Further, the central and peripheral nervous systems regulate bone mass in response to strain through alterations in autonomic tone. This suggests the potential for interplay between bone and other organs via endocrine signaling and autonomic innervation. In this study, our group investigated this potential interplay by focusing on bone and heart. We hypothesized that mechanical bone loading of mice in vivo would result in altered cardiac function. To test this hypothesis, we performed acute in vivo mechanical loading on right leg tibias of anesthetized TOPGAL and CD-1 mice. Tibias underwent compressive cyclic loading (a sine wave) that modulates between -0.3N and -9.0N for 300 cycles at 2 Hz. Cardiac function was monitored with lead II electrocardiogram (ECG) data, heart rate (HR), and heart rate variability (HRV). Immediate, transient reduction in resting HR (0.93 ± 0.013 fold change from baseline, n=6-7, p&lt;0.01 compared to control) was achieved during tibial loading in 6-month-old male and female mice, with concurrent increase in HRV (1.24 ± 0.11 fold change from baseline, n=6-7, p&lt;0.01). Both HR and HRV returned to baseline levels upon completion of the loading process. ECG measurements, QRS and corrected QT (QTc), were not found to be altered (p&gt;0.05) during loading and 30 minutes following loading. In further studies, 1N-2N did not produce a decrease in HR, while 3N (0.92 ± 0.077 fold change from baseline, n=12, p&lt;0.05) and 9N (0.93 ± 0.061 fold change from baseline, n=13, p&lt;0.05) decreased HR. There was decreased magnitude and responsiveness with aging to 11 months old at 3N and 9N (p&gt;0.05), suggesting the response may weaken with age. The immediate, transient nature of the changes to resting HR and HRV suggest a neural mechanism for this response. To test this mechanism, we inhibited local neuronal afferent activity by injecting lidocaine (2.5mg/kg) near the tibia prior to loading. In doing so, the decrease in HR during loading was significantly diminished (vehicle 0.90 ± 0.060 vs. lidocaine 0.97 ± 0.042 fold change from baseline, n=7-8, p&lt;0.05). To test the efferent arm of the response, mice were injected with the parasympathetic, muscarinic acetylcholine receptor antagonist atropine (2mg/kg), or the sympathetic, β1/β2 receptor antagonist propranolol (10mg/kg). Propranolol significantly inhibited the HR decrease during loading (vehicle 0.88 ± 0.095 vs. propranolol 0.98 ± 0.026 fold change from baseline, n=7-8, p&lt;0.05), while atropine did not (n=8-11, p&gt;0.05). These findings suggest that reductions in sympathetic tone on the heart during bone loading led to the decrease in HR. In conclusion, this study uncovered a reflexive neural connection between bone and heart that is affected by age and mediated by afferent neurons in the tibia and alterations in efferent sympathetic tone to the heart. These findings provide new knowledge that builds on the current science of bone remodeling and its regulation. This study was funded by HRSA Medical Student Education Grant T99HP39202 and NIH P01AG039355. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Right iliopsoas kaposiform hemangioendothelioma: a case report

BackgroundKaposiform hemangioendothelioma (KHE) is a rare neoplasm of vascular origin. It may involve skin, bone, connective tissue, and parenchymal organs, and it is difficult to make a definite diagnosis in the early stage because Kasabach-Merritt phenomenon may occur in some cases.Case presentationOn June 12, 2022, a 19-month boy was admitted to our department with the chief complaint of flexion of the right hip joint for over 1 year. An exploratory laparotomy and pelvic lesion resection were conducted and the resection of the iliopsoas muscle mass was performed. The intraoperative resection of the neoplasm confirmed the pathological diagnosis of kaposiform hemangioendothelioma. The vital signs of the child were stable and recovered well after surgery, and the platelet and coagulation indices were normal.ConclusionKHE is a rare disease in clinics, the number of confirmed cases in the world is still relatively few, and the etiology and mechanism of the disease are still unknown, which could result in misdiagnose and delayed treatment in the disease early stages. It is necessary to continue to collect relevant cases, to unify the standard treatment guidelines as soon as possible, to reduce the mortality rate, and to improve the quality of life of the cases.

3-[18F]Fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG) PET-A Novel Imaging Modality for Paraganglioma.

Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment. This work aimed to evaluate a novel PET radiotracer, 3-[18F]fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL. 3-[18F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.6 ± 17.6 years; range, 19-74 years) with pathologically confirmed or clinically diagnosed PCC/PGL. After intravenous administration of 304 to 475 MBq (8.2-12.8 mCi) of 3-[18F]pHPG, whole-body PET scans were performed at 90 minutes in all patients. 3-[18F]pHPG PET was interpreted for abnormal findings consistent with primary tumor or metastasis, and biodistribution in normal organs recorded. Standardized uptake value (SUV) measurements were obtained for target lesions and physiological organ distributions. 3-[18F]pHPG PET showed high radiotracer uptake and trapping in primary tumors, and metastatic tumor lesions that included bone, lymph nodes, and other solid organ sites. Physiological biodistribution was universally present in salivary glands (parotid, submandibular, sublingual), thyroid, heart, liver, adrenals, kidneys, and bladder. Comparison [68Ga]DOTATATE PET/CT was available in 10 patients and in all cases showed concordant distribution. Comparison [123I]meta-iodobenzylguanidine [123I]mIBG planar scintigraphy and SPECT/CT scans were available for 4 patients, with 3-[18F]pHPG showing a greater number of metastatic lesions. We found the kinetic profile of 3-[18F]pHPG PET affords high activity retention within benign and metastatic PCC/PGL. Therefore, 3-[18F]pHPG PET imaging provides a novel modality for functional imaging and staging of malignant paraganglioma with advantages of high lesion affinity, whole-body coregistered computed tomography, and rapid same-day imaging.

Proteoglycans in mechanobiology of tissues and organs: Normal functions and mechanopathology

AbstractProteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM), where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels, and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity, and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage‐sensitive ion channels, transient receptor potential, and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context‐specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac muscle, and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and in vitro cell culture experiments with three‐dimensional organoid models. These studies have helped to elucidate the tissue‐specific roles that PGs play in cell‐level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.

Epidemiological data, etiology, pathogenesis, risk factors, clinical manifestations, modern methods of diagnosis and treatment, prediction of the course of multiple myeloma (literature review)

Background. Multiple myeloma (MM) is a neoplastic disease with a multistage course characterized by uncontrolled, multifocal proliferation of monoclonal plasma cells in the bone marrow, which produce monoclonal immunoglobulin or only its fragments, which lead to destruction of bone tissue and organ damage. Quite high rates of both morbidity and mortality from MM require more careful attention and deeper scientific research of this problem. Objective of the article is to investigate the epidemiology, etiology, pathogenesis, risk factors, clinical manifestations, modern methods of diagnosis and treatment, and also prediction of the course of MM. Methods. The following research methods were used: search, extraction and processing of information; assessment of the quality of sources; systematic literature review; content analysis. Research materials are thematic publications of ukrainian and foreign scientists. Results. MM accounts for ~1% of all malignant neoplasms and ~14% of hematological neoplasms worldwide. Etiological factors of MM: genetic predisposition, bacterial or viral infections, ionizing radiation, carcinogenic toxins. The clinical syndrome of MM is characterized by hypergammaglobulinemia, hypercalcemia, susceptibility to infections, and pathological fractures. Diagnosis of MM includes: general analysis of peripheral blood; diagnosis of serum and urine proteins; aspiration biopsy and trepanobiopsy of bone marrow; cytogenetic and molecular diagnostics; other laboratory diagnostics; radiography, CT, MRT and PET-CT. The main methods of treatment of MM: radiation therapy, chemotherapy, combined CT with the inclusion of new drugs, HDCT + autologous THSC. Prediction of the course of MM depends on the R-ISS stage, LDH level and high-risk cytogenetics. Conclusion. During the last years of modern oncohematology, we observe scientific achievements in the diagnosis and treatment of MM. A thorough study of the epidemiology, etiology and pathogenesis, risk factors and clinical manifestations of MM contribute to effective diagnosis and selection of the optimal treatment strategy and tactics, as well as determining the prognosis of the course of MM.

Antibiotic resistance of P. aeruginosa in the presence and absence of pyocyanin pigment

Purpose: study of antibiotic resistance of Р. aeruginosa strains in the presence and absence of pyocyanin pigment. Materials and methods. Bacteriological studies of pathological material from "asphyxiated embryos", sick chickens and forcibly killed or dead adult birds were carried out according to generally accepted methods. Cultures from bone, brain, heart, liver, spleen, gall bladder, muscles and other organs were carried out on simple, selective and differential diagnostic nutrient media. The sensitivity of P. aeruginosa isolates to antibacterial drugs was determined by diffusion in agar according to the generally accepted method. The results. The obtained results of studies by the diffusion method in agar indicate that the proportion of resistant to the studied antibiotics among non-pigmented isolates was on average 79.00 % (60-100) %, and among strains that formed pyocyanin - 51.00 % (25-100) %. 60.00 % - 90.00 % of resistant non-pigmented isolates were found to fluoroquinolones, 60.00-70.00 % to cephalosporins, 60.00-97.00 % to aminoglycosides. To representatives of semisynthetic penicillins, tetracyclines, and macrolides - 100 % of resistant isolates that did not synthesize pyocyanin were found. Among P. aeruginosa isolates that synthesized pigment, 25.00-40.00 % were resistant to fluoroquinolones, 30.00-35.00 % to cephalosporins, 25.00-50.00 % to aminoglycosides, representatives semi-synthetic penicillins, tetracyclines, macrolides - 100 % of the studied strains. Conclusions. The absence of pigment formation in P. aeruginosa isolates, obtained in association with bacterial pathogens, is not accompanied by the absence of antibiotic resistance. 28 % more antibiotic-resistant isolates were found among non-pigmented isolates compared to isolates that synthesize pyocyanin pigment. The data presented emphasize the need for the use of differential media for the isolation of P. aeruginosa in order to identify non-pigmented strains and prescribe appropriate treatment, which, accordingly, will prevent the spread of latent forms of infection

A Pilot Study on Bioaccumulation and Tissue Distribution of Mercury in Barn Swallow (Hirundo rustica).

Although extensive research has been carried out on the occurrence of mercury (Hg) in biota, bioaccumulation and tissue distribution of Hg in songbirds have not been well characterized. In the present study, Hg was investigated in insects and barn swallows (Hirundo rustica) to explore the bioaccumulation characteristics of Hg. Hg in swallow feathers and tissues including muscle, liver, and bone was investigated to determine the tissue distribution of Hg. The concentrations of Hg were 1.39 ± 1.01 μg/g, 0.33 ± 0.09 μg/g, 0.47 ± 0.10 μg/g, and 0.23 ± 0.09 μg/g in feather, muscle, liver, and bone samples, respectively. The trophic magnification factor of Hg in swallows and insects was higher than 1. However, the Hg concentrations in swallow feathers were not significantly correlated with stable isotope values of carbon or nitrogen, which implies the complex food sources and exposure processes of Hg for swallows. Feathers had significantly higher concentrations of Hg than liver, muscle, and bone samples (p < 0.01 for all comparisons). Feather, muscle, bone, and other organs had fractions of 64.4 ± 11.9%, 6.07 ± 2.06%, 20.0 ± 8.19%, and 9.56 ± 2.96% in total body burden of Hg in swallows. Hg in feathers contributed more than half of Hg in the whole body for most swallow individuals. Swallows may efficiently eliminate Hg by molting, and the excretion flux of Hg and other contaminants via molting deserves more investigation.

The novel cytotoxic polybisphosphonate osteodex decreases bone resorption by enhancing cell death of mature osteoclasts without affecting osteoclastogenesis of RANKL-stimulated mouse bone marrow macrophages

SummaryIt has previously been demonstrated that the polybisphosphonate osteodex (ODX) inhibits bone resorption in organ-cultured mouse calvarial bone. In this study, we further investigate the effects by ODX on osteoclast differentiation, formation, and function in several different bone organ and cell cultures. Zoledronic acid (ZOL) was used for comparison. In retinoid-stimulated mouse calvarial organ cultures, ODX and ZOL significantly reduced the numbers of periosteal osteoclasts without affecting Tnfsf11 or Tnfrsf11b mRNA expression. ODX and ZOL also drastically reduced the numbers of osteoclasts in cell cultures isolated from the calvarial bone and in vitamin D3–stimulated mouse crude bone marrow cell cultures. These data suggest that ODX can inhibit osteoclast formation by inhibiting the differentiation of osteoclast progenitor cells or by directly targeting mature osteoclasts. We therefore assessed if osteoclast formation in purified bone marrow macrophage cultures stimulated by RANKL was inhibited by ODX and ZOL and found that the initial formation of mature osteoclasts was not affected, but that the bisphosphonates enhanced cell death of mature osteoclasts. In agreement with these findings, ODX and ZOL did not affect the mRNA expression of the osteoclastic genes Acp5 and Ctsk and the osteoclastogenic transcription factor Nfatc1. When bone marrow macrophages were incubated on bone slices, ODX and ZOL inhibited RANKL-stimulated bone resorption. In conclusion, ODX does not inhibit osteoclast formation but inhibits osteoclastic bone resorption by decreasing osteoclast numbers through enhanced cell death of mature osteoclasts.