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Falls remain common health problems that our elderly population has to face in their daily life, contributing significantly to their morbidity. Patients with astasia-abasia should be recognized promptly though it is uncommon in Singapore. We report a case of a middle-aged lady who presented with psychogenic astasia-abasia. We will illustrate this case with the exhibition of a video showing her gait pre- and post-interventions. Consent was obtained from the patient. Our patient received a multi- disciplinary level of care, including physiotherapy and psycho-education with good response. We performed a non-systematic literature review and we hereby review its description and management.

Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system. An analysis of skeletal stem cells in mice reveals that bone ageing occurs at the level of local niches affecting skeletal and haematopoietic lineage output, which may influence systemic aspects of multi-organ physiological ageing.

AIM Clinical presentation with large bowel obstruction has been proposed as a predictor of poor long-term oncological outcomes after resection for colorectal cancer. This study examines the association between obstruction and recurrence and cancer-specific death after resection for colon cancer. METHOD Consecutive patients who underwent resection for colon cancer between 1995 and 2014 were drawn from a prospectively recorded hospital database with all surviving patients followed for at least 5 years. The outcomes of tumour recurrence and colon cancer-specific death were assessed by competing risks multivariable techniques with adjustment for potential clinical and pathological confounding variables. RESULTS Recurrence occurred in 271 of 1485 patients who had a potentially curative resection. In bivariate analysis, obstruction was significantly associated with recurrence [hazard ratio (HR) 2.23, CI 1.52-3.26, p

Supplemental Digital Content is available in the text., SP142 programmed cell death ligand 1 (PD-L1) status predicts response to atezolizumab in triple-negative breast carcinoma (TNBC). Prevalence of VENTANA PD-L1 (SP142) Assay positivity, concordance with the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay, and association with clinicopathologic features were assessed in 447 TNBCs. SP142 PD-L1 intraobserver and interobserver agreement was investigated in a subset of 60 TNBCs, with scores enriched around the 1% cutoff. The effect of a 1-hour training video on pretraining and posttraining scores was ascertained. At a 1% cutoff, 34.2% of tumors were SP142 PD-L1 positive. SP142 PD-L1 positivity was significantly associated with tumor-infiltrating lymphocytes (P

Background: The atherosclerotic plaque is a complex niche composed of immune cells including T cells and macrophages as well as vascular smooth muscle cells. How T cells interact with the plaque microenvironment is not well understood. Objective: To map the crosstalk between T cells, macrophages, and smooth muscle cells. Methods/Results: We performed single cell RNAseq using the 10x transcriptomics platform in coronary plaque samples from 12 patients, who underwent heart transplantation. We found a high proportion of macrophages as well as T cells, many of which display a memory phenotype that was confirmed by immunohistochemistry. Ligand-receptor computational analysis demonstrated significant cross talk between T cells, macrophages, and smooth muscle cells. One cytokine of interest is amphiregulin (AREG), which has been shown to mediate tissue healing and fibrosis. Of note, AREG expression appears to increase as coronary plaques progress from early lipid-rich stages to more advanced stages. To elucidate the effects of AREG on smooth muscle cells, we treated human coronary artery smooth muscle cells (hCASMCs) in vitro with recombinant AREG and found increased cell proliferation compared to control (P Conclusion: Taken together, our findings suggest that cross talk between T cells and smooth muscle cells, partially through AREG production by T cells, may contribute to plaque progression.

Background: Vascular thrombosis has been described in patients actively infected with influenza and, more recently, with the coronavirus. The risk may persist during the convalescence period. The underlying mechanisms mediating these events remain unclear. Objective: To determine whether human coronary plaque T cells reactive to influenza virus are also activated by self-proteins. Methods/Results: Using single cell targetRNAseq, we mapped the T cell repertoire in 19 patients with a range of coronary artery disease severity. To determine the potential peptides activating coronary plaque T cell receptors (TCRs), we matched TCR alpha and beta identity with HLA restriction to a database of known specificities. We found that plaque TCRs were potentially activated by viral epitopes, including those from the influenza M1 protein. We used a computational algorithm to identify self-proteins in the endothelial cells and vascular smooth muscle cells that may have peptides with similar homologies to viral epitopes predicted to bind our plaque TCRs. We then introduced plaque TCRs into the Jurkat T cells, exposed these cells to T2 (HLA-2 antigen presenting cells), viral peptides (e.g., M1) and self-epitopes (e.g., TSPAN17; ZIP9), and demonstrated T cell cross reactivity in vitro ( Figure 1 ). TSPAN17 is a transmembrane protein that regulates VE-cadherin expression and promotes T cell transmigration. Zip9, in contrast, is a protein that regulates zinc homeostasis, serves as an androgen receptor on endothelial cells, and has been shown to promote endothelial proliferation. Conclusion: Taken together, our findings suggest that T cell cross reactivity may be a potential mediator of viral-induced arterial thrombosis.

Background: Atherosclerosis is considered a chronic inflammatory disorder characterized by the presence of T cells and macrophages in the plaque. Given that T cells are the master regulators of the immune system, the possible role of T cells in mediating disease warrants further investigation. Objective: To map the T cell transcriptome in coronary artery plaque. Methods/Results: Using single cell RNAseq, we mapped the transcriptome of immune cells within the coronary atherosclerotic plaque in 12 patients with various disease stages. In addition to macrophages, we find an abundance of plaque T cells that appear to be enriched in plaque compared to blood ( Figure 1A ). Two plaque-enriched CD8 effector memory clusters (CD8 CTL Tem1 and CD8 CTL Tem2) display the highest proportion of activated cells (e.g., HLA-DRA+). These clusters are characterized by high expression of the pro-inflammatory cytokines (e.g., CCL3, CCL4, CCL5, and IFNG) and cytolytic markers (e.g.,GZMA, GZMH, GZMM, NKG7). CD8 CTL Tem1, however, has higher expression of GZMK, a cytolytic marker recently associated with inflammaging. CD8 CTL Tem2, on the other hand, has a higher expression of perforin and granulysin, two pore-forming proteins that mediate cell killing by enabling granzyme entry. Notably, CD8 CTL Tem2 appears to track with plaque progression, increasing as plaques mature from lipid-rich to more complex lesions then declining as plaques became more stable and calcified post-rupture. Specifically, this cluster displayed two-fold enrichment in complex plaques compared to other plaque phenotypes (12.1% vs. 6.9%, p=0.0069) ( Figure 1B ). This pro-inflammatory and cytolytic signature is also more apparent in the activated compared to nonactivated cells in this cluster. Conclusion: Taken together, our findings suggest that a pro-inflammatory CD8 T cell cluster characterized by a trifecta of cytolytic enzymes distinguishes complex plaque and deserves further investigation.

Objective To examine the independent prognostic value of ALN status in patients with stage III CRC. Summary of background data Early CRC staging classified nodal involvement by level of involved nodes in the operative specimen, including both locoregional and apical node status, in contrast to the American Joint Committee on Cancer/tumor nodes metastasis (TNM) system where tumors are classified by the number of nodes involved. Whether ALN status has independent prognostic value remains controversial. Methods Consecutive patients who underwent curative resection for Stage III CRC from 1995 to 2012 at Concord Hospital, Sydney, Australia were studied. ALN status was classified as: (i) ALN absent, (ii) ALN present but not histologically involved, (iii) ALN present and involved. Outcomes were the competing risks incidence of CRC recurrence and CRC-specific death. Associations between these outcomes and ALN status were compared with TNM N status results. Results In 706 patients, 69 (9.8%) had an involved ALN, 398 (56.4%) had an uninvolved ALN and 239 (33.9%) had no ALN identified. ALN status was not associated with tumor recurrence [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43). However, associations persisted between TNM N-status and both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12). Conclusions No further prognostic information was conferred by ALN status in patients with stage III CRC beyond that provided by TNM N status. ALN status is not considered to be a useful additional component in routine TNM staging of CRC.

Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2–4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5–7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA. Endogenous skeletal stem cells are recruited to form cartilage in mice when stimulated by microfracture surgery together with localized delivery of growth factors, pointing to a new approach for treating cartilage defects.

Summary Osteoporosis and osteoporotic fractures lead to decreased life quality and high healthcare costs. Current treatments prevent losses in bone mass and fractures to some extent but have side effects. Therefore, better therapies are needed. This study investigated whether the transcription factor Jun has a specific pro-osteogenic potency and whether modulating Jun could serve as a novel treatment for osteoporosis-associated fractures. We demonstrate that ectopically transplanted whole bones and distinct osteoprogenitors increase bone formation. Perinatal Jun induction disturbs growth plate architecture, causing a striking phenotype with shortened and thickened bones. Molecularly, Jun induces hedgehog signaling in skeletal stem cells. Therapeutically, Jun accelerates bone growth and healing in a drilling-defect model. Altogether, these results demonstrate that Jun drives bone formation by expanding osteoprogenitor populations and forcing them into the bone fate, providing a rationale for future clinical applications., Graphical Abstract, Highlights • Jun drives the formation of bone at the expense of cartilage and stroma • Jun disturbs the proper differentiation of the developing growth plate • Jun stimulates hedgehog signaling in skeletal stem cells • Jun accelerates fracture healing in a drilling-defect model, Wernig and colleagues demonstrate the striking potency of the transcription factor Jun to expand bone precursors, drive bone formation, and accelerate fracture healing. Boosting the regenerative potential of dormant bone precursor cells, they show the potential of stem cell therapy for widespread degenerative disease.

Aim Despite numerous reports over three decades, the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer remains controversial. This cohort study used competing risks statistical methods to examine the association between transfusion and recurrence and colorectal cancer-specific death after potentially curative and noncurative resection. Method A hospital database provided prospectively recorded clinical, operative and follow-up information. All surviving patients were followed for at least 5 years. Data were analysed by multivariable competing risks regression. Results From 2575 patients in the period 1995-2010 inclusive, after exclusions, 2334 remained for analysis. Among 1941 who had a potentially curative resection and 393 who had a noncurative resection the transfusion rates were 24.9% and 33.6%, respectively. After potentially curative resection there was no significant bivariate association between transfusion and recurrence (HR 0.93, CI 0.74-1.16, P = 0.499) or between transfusion and colorectal cancer-specific death (HR 1.04, CI 0.82-1.33, P = 0.753). After noncurative resection there was no significant association between transfusion and cancer-specific death (HR 0.93, CI 0.73-1.19, P = 0.560). Multivariable models showed no material effect of potential confounder variables on these results. Conclusion The competing risks findings in this study showed no significant association between perioperative transfusion and recurrence or colorectal cancer-specific death.

The approach to oculomotor nerve palsies involves the exclusion of compressive, infective, inflammatory, or ischemic lesions. Dural arteriovenous fistulae, including carotid-cavernous fistulae (CCF), are known causes of third nerve palsy. However, diagnosis can sometimes be delayed or missed due to the various clinical presentations. CCF remains a rare but treatable cause of third nerve palsy.A 63-year-old Chinese female presented to our unit with gradual onset horizontal diplopia. Clinical examination revealed a partial left oculomotor nerve palsy without congestive eye symptoms. A cerebral angiogram revealed a left indirect CCF supplied by the inferolateral trunk of the left internal carotid artery. She underwent successful transvenous embolization. She improved postprocedure and was discharged well on day 10 of her admission. She was reviewed at 2 months follow-up and had recovered completely.Our case is a classic description of a CCF with posterior drainage into the inferior petrosal sinus. We hope this case and a review of the literature can serve as a reminder to clinicians of the varied presentations of CCF. We believe this case adds value to the clinicians in contributing to their diagnostic process and to our interventional colleagues in highlighting a case with a successful postembolization outcome.

The concept that right and left sided colorectal cancer may be biologically different has led to a review of the pathology and molecular characteristics expressed by the two sides. The aim of this cross-sectional study was to examine the association between tumour sub-sites and the presence of any metastasis by multivariable modelling. Pathology data were drawn from a hospital series of 3360 consecutive patients who had their first cancer resected between 1995 and 2019 inclusive. A preliminary analysis of the distribution of sex, age and a range of routinely reported pathology features showed that the simple division of the bowel into right and left sides masks the considerable variation in pathology features which occurs between sub-sites within each side. Logistic regression adjusting for sex, age, a range of routinely reported pathology features and tumour sub-site showed that age ≤70, direct tumour spread (T3 and T4), high grade, venous invasion and perineural invasion all carried a significantly increased risk for the presence of metastatic spread. The only tumour sub-sites to show an increased risk were the sigmoid colon and rectum (adjusted odds ratio 1.72, P 0.001 and 1.78, P 0.001, respectively). These findings suggest that multivariable modelling could usefully be applied to identify associations between sub-sites and molecular characteristics.

The tendon enthesis plays a critical role in facilitating movement and reducing stress within joints. Partial enthesis injuries heal in a mechanically inferior manner and never achieve healthy tissue function. The cells responsible for tendon-to-bone healing remain incompletely characterized and their origin is unknown. Here, we evaluated the putative role of mouse skeletal stem cells (mSSCs) in the enthesis after partial-injury. We found that mSSCs were present at elevated levels within the enthesis following injury and that these cells downregulated TGFβ signaling pathway elements at both the RNA and protein levels. Exogenous application of TGFβ post-injury led to a reduced mSSC response and impaired healing, whereas treatment with a TGFβ inhibitor (SB43154) resulted in a more robust mSSC response. Collectively, these data suggest that mSSCs may augment tendon-to-bone healing by dampening the effects of TGFβ signaling within the mSSC niche.

Recent developments in our understanding of molecular genetics have transformed screening and diagnostic practices for Lynch syndrome. The current standard involves universal tumour analysis of resected colorectal cancer (and ideally polypectomy) specimens using immunohistochemistry and molecular techniques. Patients with abnormal immunohistochemical findings are subsequently referred for definitive mutational testing. This review relates the molecular pathogenesis of Lynch syndrome to current immunohistochemistry-based screening strategies and discusses the interpretation and clinical implications of screening results.

Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. This study investigates whether skeletal stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures. Transcriptomic analysis highlights a distinct signature in cells derived from the physiological closing PF suture, and scRNA sequencing identifies transcriptional heterogeneity among sutures. Wnt-signaling activation increases skeletal stem/progenitor cells in sutures, whereas its inhibition decreases. Crossing Axin2LacZ/+ mouse, endowing enhanced Wnt activation, to a Twist1+/− mouse model of coronal craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Co-transplantation of these cells with Wnt3a prevents resynostosis following suturectomy in Twist1+/− mice. Our study reveals that decrease and/or imbalance of skeletal stem/progenitor cells representation within sutures may underlie craniosynostosis. These findings have translational implications toward therapeutic approaches for craniosynostosis., Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

With the dramatic increase in data traffic envisioned for the next years, operator’s network will be requested to sustain a large amount of data traffic, while at the same time being more flexible easily upgradable and having a lower total cost ownership (TCO). The industry at large is shifting towards SDN architectures, with white-box devices and open source software as building blocks. Such trend allows for further optimization across network layers, packet and optical as an example, with shared infrastructure and control. In this paper, we demonstrate a full end-to-end multi-stage data-center solution, combining leaf-spine control from Trellis, dedicated optical link provisioning by ODTN, and switches and packet optical programmable devices managed by Stratum.Unifying optical and Ethernet capabilities, the Cassini packet-optical transponder acts as a spine in the intra data-center Trellis leaf spine topology, and as the transponder for the DCI inter data-center links.We will describe the implemented architecture, the overall topology, the changes required to achieve the end to end solution and the challenges faced. We then outline the benefits of the proposed solution in terms of resource consumption, end to end optimisation, reliability and resiliency based upon data collected in a physical setup at ONF. Finally, we conclude this paper with future work and proposed optimisations.

The skeletal system is a highly complex network of mesenchymal, hematopoietic, and vasculogenic stem cell lineages that coordinate the development and maintenance of defined microenvironments, so-called niches. Technological advancements in recent years have allowed for the dissection of crucial cell types as well as their autocrine and paracrine signals that regulate these niches during development, homeostasis, regeneration, and disease. Ingress of blood vessels and bone marrow hematopoiesis are initiated by skeletal stem cells (SSCs) and their more committed downstream lineage cell types that direct shape and form of skeletal elements. In this chapter, we focus on the role of SSCs as the developmental origin of niches for hematopoietic stem and progenitor cells. We discuss latest updates in the definition of SSCs, cellular processes establishing and maintaining niches, as well as alterations of stem cell microenvironments promoting malignancies. We conclude with an outlook on future studies that could take advantage of SSC-niche engineering as a basis for the development of new therapeutic tools to not only treat bone-related diseases but also maladies stemming from derailed niche dynamics altering hematopoietic output.

Gelatin methacryloyl (GelMA)/alginate-based hydrogels have shown great promise in bioprinting, but their printability is limited at room temperature. In this paper, we present our development of a room temperature printable hydrogel bioink by introducing polyethylene glycol dimethacrylate (PEGDMA) and xanthan gum into the GelMA/alginate system. The inclusion of PEGDMA facilitates tuning of the hydrogel's mechanical property, while xanthan gum improves the viscosity of the hydrogel system and allows easy extrusion at room temperature. To fine-tune the mechanical and degradation properties, methacrylated xanthan gum was synthesized and chemically crosslinked to the system. We systematically characterized this hydrogel with attention to printability, strut size, mechanical property, degradation and cytocompatibility, and achieved a broad range of compression modulus (∼10-100 kPa) and degradation profile (100% degradation by 24 h-40% by 2 weeks). Moreover, xanthan gum demonstrated solubility in ionic solutions such as cell culture medium, which is essential for biocompatibility. Live/dead staining showed that cell viability in the printed hydrogels was over 90% for 7 days. Metabolic activity analysis demonstrated excellent cell proliferation and survival within 4 weeks of incubation. In summary, the newly developed hydrogel system has demonstrated distinct features including extrusion printability, widely tunable mechanical property and degradation, ionic solubility, and cytocompatibility. It offers great flexibility in bioprinting and tissue engineering.

Background: Despite advances in medical therapy, heart attack and stroke remain leading causes of morbidity and mortality. Biological, epidemiological, and clinical studies have shown that many patients (up to 33% in some trials) still have residual inflammatory risk that is associated with plaque rupture, even in the setting of low LDL. Methods and Results: In this study, we analyzed the T cell landscape of coronary atherosclerotic plaque to determine their role in the development of atherosclerosis and its adverse sequelae. We recruited 17 patients undergoing heart transplantation. From each explanted heart, we obtained plaques from the major coronary arteries, digested them to form a single cell suspension, sorted the arteries for CD4 and CD8 T cells into 96 well plates, and submitted them for single cell genotyping and phenotyping ( Figure 1 ). Although peripheral blood from these patients also contains T cell clones, plaque CD8 T cell clones appear to function differently than blood (e.g., producing more BCL6, TNF-, and interferon gamma) further supporting that this is not a bystander effect. We found CD4 and CD8 T cells with identical TCR sequence across the arteries of the same patient, suggesting CD8T cells are purposely recruited to the plaques. When we analyzed the percent clonality based upon location and disease severity, we find that clonality is not dependent on location and is present at all severity levels, especially, in early disease (e.g., AHA Type I-IV lesions. Conclusion: CD8 T cells are clonally expanded in atherosclerotic plaque and appear to function differently than blood, suggesting these cells are purposefully recruited.

Delayed union or nonunion are relatively rare complications after fracture surgery, but when they do occur, they can result in substantial morbidity for the patient. In many cases, the etiology of impaired fracture healing is uncertain and attempts to determine the molecular basis for delayed union and nonunion formation have been limited. Prospectively isolating skeletal stem cells (SSCs) from fracture tissue samples at the time of surgical intervention represent a feasible methodology to determine a patient's biologic risk for compromised fracture healing. This report details a case in which functional in vitro readouts of SSCs derived from human fracture tissue at time of injury predicted a poor fracture healing outcome. This case suggests that it may be feasible to stratify a patient's fracture healing capacity and predict compromised fracture healing by prospectively isolating and analyzing SSCs during the index fracture surgery. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age‐related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites (n = 61) of patients ranging from 13 to 94 years of age for functional and molecular studies. We observed that fracture‐activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence‐related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re‐activation by trans‐resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age‐related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans., Human skeletal stem cells (hSSCs) are present and accumulate at fracture sites independent of age. Impaired healing in the elderly might underlie functional defects in hSSCs which are exacerbated in women. Re‐activation of Sirt1 rejuvenates geriatric hSSCs independent of sex.

Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter’s ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses., Professional antigen presenting cells (APCs) are deterred from phagocytosing cancer cells that express CD47. Here, the authors show that in glioblastoma mouse models, temozolomide improves the phagocytosis effect of CD47 blockade in APCs and results in the activation of adaptive anti-tumour responses.

Conventionally, lymphatic spread is regarded as the principal mechanism by which haematogenous metastasis occurs in colorectal cancer. The aim of this cross sectional study was to determine the relative strengths of direct tumour spread, the presence of lymph node metastasis and histologically demonstrated venous invasion as drivers of haematogenous metastasis diagnosed at the time of resection of colorectal cancer. The data were drawn from a hospital database of consecutive bowel cancer resections between 1995 and 2017 inclusive. The presence of haematogenous metastasis was determined at the time of surgery by imaging or other investigations or operative findings. Where possible, histological confirmation was obtained. Specimen dissection and reporting followed a standardised procedure. Tumour staging was according to the 7th edition of the UICC/AJCC pTNM system. Analysis was by multivariable logistic regression. After exclusions 3133 patients remained, among whom 380 (12.1%) had one or more haematogenous metastases. In bivariate analyses, the frequency of haematogenous metastasis was directly associated with increasing T status (p