Cell-type-specific functions and identity are tightly regulated by interactions between the cell cytoskeleton and the extracellular matrix (ECM). Human pluripotent stem cells (hPSCs) have ultimate differentiation capacity and exceptionally low-strength ECM contact, yet the organization and function of adhesion sites and associated actin cytoskeleton remain poorly defined. We imaged hPSCs at the cell-ECM interface with total internal reflection fluorescence microscopy and discovered that adhesions at the colony edge were exceptionally large and connected by thick ventral stress fibers. The actin fence encircling the colony was found to exert extensive Rho-ROCK-myosin-dependent mechanical stress to enforce colony morphology, compaction, and pluripotency and to define mitotic spindle orientation. Remarkably, differentiation altered adhesion organization and signaling characterized by a switch from ventral to dorsal stress fibers, reduced mechanical stress, and increased integrin activity and cell-ECM adhesion strength. Thus, pluripotency appears to be linked to unique colony organization and adhesion structure.

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

Summary: This cross-sectional study investigated osteosarcopenia prevalence and its correlates among 2506 adults aged 55 and older in Finland. Findings show 3.9% had osteosarcopenia, while 13.8% and 11.1% had probable sarcopenia only or osteoporosis only, respectively. Osteosarcopenia was associated with low BMI, impaired mobility, ADL limitations and depression. Sarcopenia appeared to drive these associations more than osteoporosis. Osteosarcopenia may be a risk factor for functional decline, hospitalization, and institutionalization, warranting further research. Purpose: Osteosarcopenia is a disorder consisting of concurrent osteoporosis and sarcopenia. This cross-sectional study using nationally representative data from Finland in 2000 aimed to determine the prevalence of osteosarcopenia in Finland. In addition, associations of sociodemographic, lifestyle, anthropometric, physical and mental function indicators, chronic conditions and various biomarkers with osteosarcopenia were examined. Methods: The study included 2506 subjects aged 55 and over (mean age 68.0 years, SD 9.0). Probable sarcopenia was defined as grip strength < 27 kg for men and < 16 kg for women. Osteoporosis was defined as either ultrasound-based bone density measurement of T < -2.5, or self-reported, pre-existing diagnosis of osteoporosis. Participants were categorized into 4 groups: no sarcopenia and no osteoporosis, probable sarcopenia only, osteoporosis only, and osteosarcopenia. Information on sociodemographic, lifestyle, anthropometric, physical and mental function indicators, chronic conditions and various biomarkers were collected via structured interview, questionnaires, clinical examination, and blood and urine samples. Results: The prevalence of probable sarcopenia, osteoporosis and osteosarcopenia was 13.8%, 11.1%, and 3.9%, respectively. Osteosarcopenia was associated with low BMI, slow gait speed, impaired mobility, impaired ability in the activities of daily living and depression. Of the two components, probable sarcopenia appeared to contribute to these associations more than osteoporosis. Conclusion: According to representative population-based study, about every fifth person with probable sarcopenia also has osteoporosis. Mobility and ADL limitations were more common among people with osteosarcopenia than those with osteoporosis or probable sarcopenia alone. Future studies are needed to examine osteosarcopenia as an independent risk factor for functional decline, hospitalization, and institutionalization.

Purpose: This study assessed osteoporosis, sarcopenia and osteosarcopenia as risk factors for fractures and mortality during 19-year follow-up. Methods: We analyzed 2506 individuals aged ≥ 55 from the Finnish Health 2000 Survey. Probable sarcopenia was defined as grip strength < 27 kg for men and < 16 kg for women. Osteoporosis was identified by a bone density T-score < -2,5 via ultrasound or a self-reported diagnosis. Participants were categorized in four groups: reference group with no sarcopenia and no osteoporosis, probable sarcopenia only, osteoporosis only, or osteosarcopenia. Fractures and deaths were identified from national registers until 2019. Four adjustment models were used, adjusting for age, sex, smoking, education, physical activity, and mobility limitation. Results: Over a mean follow-up of 19.1 years, 580 (23.1%) participants sustained a low-energy fracture of any type and 1,375 (54.9%) died. Osteosarcopenia, probable sarcopenia and osteoporosis were all associated with increased risk of any fracture and mortality compared to the reference group. Osteoporosis alone was associated with lower mortality than osteosarcopenia (HR 0.69, 95% CI 0.50–0.95), but mortality did not differ between probable sarcopenia and osteosarcopenia (HR 0.79, 95% CI 0.59–1.06). No differences in the fracture risk between osteosarcopenia, sarcopenia and osteoporosis were observed. Conclusion: While both sarcopenia and osteoporosis increase fracture and mortality risks, their combination does not seem to additively elevate fracture risks. Osteoporosis is a stronger predictor for future fractures, whereas probable sarcopenia is more closely linked to mortality. Further research is warranted to determine the best ways to incorporate sarcopenia assessment into comprehensive fracture risk evaluation.

Background: The longitudinal associations between indicators of sarcopenia – such as muscle and functional impairments – and subsequent institutionalization and mortality after hip fracture are not well known. Aims: The aim of this study was to examine handgrip strength (HGS), calf circumference (CC), and the SARC-F questionnaire as predictors of admission to a long-term care facility (LTCF) and mortality among hip fracture patients. Methods: Study population consisted of 430 older adults with a low-energy hip fracture admitted in a university hospital between September 2021 to January 2023. Of these patients, 222 had data on HGS, CC, and the SARC-F questionnaire. Admission to an LTCF and mortality were followed for up to one year. Analyses were adjusted for age, sex, ASA score, and cognitive and nutritional status. Results: During one-year follow-up, 14% entered long-term care and 13% died. Positive SARC-F-screen significantly increased the odds of admission to LTCF (OR 8.20; 95% CI 2.34–28.7), but no association was observed for HGS or CC. Positive SARC-F screening predicted mortality (HR 3.00, 95% CI 1.11–8.07). HGS-based probable sarcopenia showed a tendency towards increased mortality in the age and sex adjusted model (HR 8.07; 95% CI 1.09–59.9), but not after adjusting for ASA score, cognitive and nutritional status (HR 7.01; 95% CI 0.93–52.6). Conclusions: The SARC-F questionnaire emerged as a strong predictor for both LTCF admission and mortality one year after hip fracture, suggesting that the SARC-F may help clinicians identify patients at highest risk after hip fracture.

Human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. Endosomal trafficking of many other receptor tyrosine kinases regulates their oncogenic signaling, but the prevailing view is that HER2 is retained on the cell surface. Here we reveal that in cancer cells Sortilin related receptor 1 (SORLA; SORL1 ) forms a complex with HER2 and regulates its subcellular distribution by promoting recycling of endosomal HER2 back to plasma membrane. Expression of SORLA in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA targets HER2 to late endosomal/lysosomal compartments, impairs HER2-driven signaling and in vivo tumor growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.