Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial.

BACKGROUND: In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. METHODS: CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. FINDINGS: Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. INTERPRETATION: Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Stress Effect in the Knee Joint Based on the Fibular Osteotomy Level and Varus Deformity: A Finite Element Analysis Study.

Proximal fibular osteotomy (PFO) was found to relieve pain and improve knee function in patients with medial compartment knee osteoarthritis (OA). Therapy redistributes the load applied from the inside to the outside and alleviates the load applied on the inside through fibula osteotomy. Therefore, the clinical effect of fibular osteotomy using the finite element (FE) method was evaluated to calculate the exact change in stress inside a knee joint with varus deformity. Using CT and MRI images of a patient's lower extremities, 3D models of the bone, cartilage, meniscus, and ligaments were constructed. The varus angle, representing the inward angulation of the knee, was increased by applying a force ratio in the medial and lateral directions. The results showed that performing proximal fibular osteotomy led to a significant reduction in stress in the medial direction of the meniscus and cartilage. The stress reduction in the lateral direction was relatively minor. In conclusion, the study demonstrated that proximal fibular osteotomy effectively relieves stress and redistributes the load in the knee joints of patients with medial compartment knee osteoarthritis. The findings emphasize the importance of considering force distribution and the position of fibular osteotomy to achieve optimal clinical outcomes.

CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.

Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.

Current Status of Human Papillomavirus-Targeted Therapies Development in Head and Neck Cancer.

PURPOSE: While the incidence of smoking-related head and neck squamous cell carcinoma (HNSCC) has been declining, that of human papillomavirus (HPV)-mediated HNSCC has rapidly increased in the past decades worldwide. Despite rapid advances in therapeutics for solid tumors with novel immunotherapy and targeted therapeutic agents, no breakthroughs have yet been made in the treatment of advanced HPV+ HNSCCs. This review aims to summarize the concepts and designs, early trial results, and future directions of various HPV-targeted experimental therapeutics for HPV+ HNSCC. MATERIALS AND METHODS: Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, a systemic literature search of PubMed was conducted for HPV-targeted therapeutics using the following search terms: HPV, head and neck squamous cell carcinoma, and therapy. For clinical trial data, publications, major oncology conference abstracts, and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov) information were reviewed. This review focused on the ones that are in the clinical stage and currently in active ongoing evaluation. The therapeutics not actively evaluated in HNSCC, in the preclinical stage, or terminated for further development were excluded. RESULTS: Diverse approaches are being actively explored to target HPV+ HNSCC, including therapeutic vaccines of various modalities, HPV-specific immune cell-activating agents, and adaptive cellular therapeutics. All these novel agents use immune-based mechanisms and target constitutively expressed oncogenic HPV E6 and/or E7 viral proteins. Most therapeutics demonstrated excellent safety but single-agent activities are only modest. Many are being tested in combination with immune checkpoint inhibitors. CONCLUSION: Our review summarized various novel HPV-targeted therapeutics that are in the clinical phase for HPV+ HNSCC. Early-phase trial data suggest the feasibility and promising efficacy. Further strategies, including selecting the optimal combination and understanding and overcoming resistant mechanisms, are warranted for successful development.

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy.

Although immunotherapy can offer profound clinical benefit for patients with a variety of difficult-to-treat cancers, many tumors either do not respond to upfront treatment with immune checkpoint inhibitors (ICIs) or progressive/recurrent disease occurs after an interval of initial control. Improved response rates have been demonstrated with the addition of ICIs to cytotoxic therapies, leading to approvals from the US Food and Drug Administration and regulatory agencies in other countries for ICI-chemotherapy combinations in a number of solid tumor indications, including breast, head and neck, gastric, and lung cancer. Designing trials for patients with tumors that do not respond or stop responding to treatment with immunotherapy combinations, however, is challenging without uniform definitions of resistance. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-programmed cell death protein 1 (PD-1). To provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of ICIs and chemotherapies. Definitions for resistance to ICIs in combination with targeted therapies and with other ICIs will be published in companion volumes to this paper.

Phase 1 study to determine the safety and dosing of autologous PBMCs modified to present HPV16 antigens (SQZ-PBMC-HPV) in HLA-A*02+ patients with HPV16+ solid tumors.

We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 - 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 - 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.

Impact of COVID-19 infection on sports performance of elite university athletes.

BACKGROUND: Cardiopulmonary functions of athletes can be affected by the Coronavirus disease 2019 (COVID-19). This study aimed to investigate athletes' pattern of returning to sports after COVID-19, their experience of COVID-19-associated symptoms, and the disturbance in sports performance caused by the symptoms. METHODS: Elite university athletes who were infected with COVID-19 in 2022 were recruited for the survey and the data for 226 respondents were analyzed. Information about COVID-19 infection and the degree of disturbance in ordinary training and competition was collected. Their returning pattern to sports, the prevalence of COVID-19 symptoms, the degree of disturbance in sports by related symptoms, and factors associated with disturbance in sports and fatigue were analyzed. RESULTS: Results showed that 53.5% of the analyzed athletes returned to ordinary training immediately after quarantine, while 61.5% experienced disturbance in ordinary training, and 30.9% experienced that in competition. Most prevalent COVID-19 symptoms were lack of energy, easy fatiguability and cough. Disturbance in ordinary training and competition were mainly related to generalized, cardiologic, and respiratory symptoms. Women and those with severe and generalized symptoms had significantly higher odds of experiencing disturbance in training. Those with cognitive symptoms had higher odds of being "fatigue case." CONCLUSIONS: More than half of the athletes returned immediately to sports after the legal quarantine period of COVID-19 infection and experienced disturbance in ordinary training by related symptoms. Prevalent COVID-19 symptoms and the associated factors causing disturbance in sports and fatigue case were also revealed. This study will be helpful to establish the safe return guidelines essential for athletes after COVID-19.

Effects of surgical factors on the outcomes of zygoma reduction malarplasty: a quantitative computed tomography study.

BACKGROUND: Malarplasty is widely performed for zygoma reduction. The effects of body segmentation, plate bending, and postoperative arch location on zygomatic movement have not been analyzed using computed tomography (CT). RESULTS: We quantitatively analyzed the effects of surgical factors on zygomatic movements via superimposition of preoperative and postoperative CT images using three-dimensional software. Our results showed that segmentation had the most significant effect on the horizontal reduction of malar eminence (ß = 0.593, r = 0.696, adjusted r2 = 0.479, F = 79.595; p < 0.001). In addition, upward and posterior arch movements had significant effects on the anterior and posterior movements of the eminence (ß = - 0.379 for vertical arch movement, ß = 0.324 for arch setback, r = 0.603, adjusted r2 = 0.352, F = 31.943; p < 0.001). The major factors that influenced inward arch movement at the coronoid process included segmentation and inward movement at the arch osteotomy site. To prevent interference of the coronoid process and arch, surgeons should pay attention to the degree of segmentation (ß = 0.349) and inward movement at the arch osteotomy site (ß = 0.494; r = 0.688, adjusted r2 = 0.464, F = 50.412; p < 0.001). CONCLUSIONS: Surgical factors related to malarplasty affect the movement of specific parts of the zygoma. In addition, accurate application is possible by considering the anatomical structure of the application area when using the bending plate.

Usefulness of hand grip strength to estimate other physical fitness parameters in older adults.

This study aimed to reveal the status of physical fitness (PF) levels and determine whether hand grip strength (HGS) could be used to estimate other PF parameters in older adults from large population data. A total of 46,269 participants aged ≥ 65 years who participated in the 2019 National Fitness Award Project in South Korea were included in the analysis. Of the participants, 6.8% had the highest level of overall physical fitness, while 48.9% had the lowest level. The proportion of overall PF levels differed significantly according to age groups. Significant associations between HGS and other PF parameters (30-s chair stand test, 2-min or 6-min walk test, sit-and-reach test, 3-m backwards walk test, and Figure-of-8 walk test) were noted and the group with low HGS (< 28 kg for men and < 18 kg for women) had significantly higher odds of having the lowest level of overall PF (odds ratio: 5.232 in men and 6.351 in women), after adjusting for age and body mass index. HGS could estimate muscular strength and endurance, aerobic fitness, flexibility, balance skills, and coordination skills, as well as overall PF level in older adults, and could be used as a substitute test for their PF level in limited situations.

The short-term effectiveness of scapular focused taping on scapular movement in tennis players with shoulder pain: A within-subject comparison.

This study aimed to investigate the short-term effectiveness of scapular focused taping (SFT) on scapular position and kinematics during the tennis serve among professional players with and without shoulder pain. The cohort included 7 players who had no history of non-shoulder pain (NSP) and 6 players with shoulder pain (SP). All participants performed tennis flat serves while the Qualisys motion capture system recorded three-dimensional scapular kinematic data according to the International Society of Biomechanics recommendations. SFT was applied to the participants' torso aligned with the lower trapezius, and the same movements were repeated. In the SP group, the scapula was tilted more posteriorly after the application of SFT as compared to before at ball release and maximally externally rotated humerothoracic joint during tennis serve (t = -5.081, P = .004 and t = -2.623, P = .047, respectively). In the NSP group, the scapula was tilted more posteriorly with SFT as compared to without at first 75% timing of the cocking phase and maximally externally rotated humerothoracic joint (t = -3.733, P = .010 and t = -2.510, P = .046, respectively). And the SP group exhibited a more rotated scapula externally after the application of SFT as compared to before at Ball impact (t = 5.283, P = .003). SFT had a positive immediate effect on the scapular posterior tilting and external rotation during certain phases of the tennis serve among tennis athletes with and without shoulder pain. These findings may help clinicians and sports practitioners to prevent and rehabilitate shoulder injuries for overhead athletes. Level of evidence: Level III; Case-Control Design; Comparative Study.

Shape suitability and mechanical safety of customised hip implants: Three-dimensional printed acetabular cup for hip arthroplasty.

Background: Owing to an increase in the number of hip arthroplasty surgeries, the number of implant replacement surgeries is increasing rapidly as well. This necessitates the study of hip joint conditions. Therefore, Paprosky defined a classification system to indicate the degree of damage to the hip joint. In this study, a customised hip implant suitable for Paprosky classification Type ⅡC and over was designed. The shape, suitability, and mechanical safety of the worst-case model for the implant were evaluated. Materials and methods: To identify the implant size depending on states over Type ⅡC acetabulum bone loss, a size range was selected and a customised implant was designed according to the computed tomography data within the size range. The implant was designed for the flange, hook, and flattened model types. The worst-case selection test was conducted using finite element analysis. The von Mises stresses of the flange, hook, and flattened models were found as 76.223, 136.99, and 80.791 MPa, respectively. Therefore, the hook-type model was selected as the worst case for the mechanical performance test. Results: A bending test was conducted on the hook-type model without fracture and failure at 5344.56 N. The proposed customised implant was found suitable for Type ⅢA acetabulum bone loss, whereas the shape suitability and mechanical safety were verified for the worst case. Conclusion: The shape of a customised implant suitable for Paprosky ⅢA type was designed. The shape suitability and mechanical safety were evaluated using finite element method analysis and bending tests. Clinical validation is required through subsequent clinical evaluation.

Current and Future Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma.

With the introduction of immunotherapy, significant improvement has been made in the treatment of head and neck squamous cell carcinoma (HNSCC). However, only a small subset of patients with HNSCC benefit from immunotherapy. The current biomarker, a programmed cell death protein ligand 1 (PD-L1) expression that is widely used in treatment decision making for advanced HNSCC, has only a moderate predictive value. Additionally, PD-L1-based assay has critical inherent limitations due to its highly dynamic nature and lack of standardization. With the advance in molecular techniques and our understanding of biology, more reliable, reproducible, and practical novel biomarkers are being developed. These include but are not limited to neoantigen/mutation characteristics, immune transcriptomes, tumor-infiltrating immune cell composition, cancer epigenomic, proteomics and metabolic characteristics, and plasma-based and organoid assays.

Preconditioning process for dermal tissue decellularization using electroporation with sonication.

Decellularization to produce bioscaffolds composed of the extracellular matrix (ECM) uses enzymatic, chemical and physical methods to remove antigens and cellular components from tissues. Effective decellularization methods depend on the characteristics of tissues, and in particular, tissues with dense, complex structure and abundant lipid content are difficult to completely decellularize. Our study enables future research on the development of methods and treatments for fabricating bioscaffolds via decellularization of complex and rigid skin tissues, which are not commonly considered for decellularization to date as their structural and functional characteristics could not be preserved after severe decellularization. In this study, decellularization of human dermal tissue was done by a combination of both chemical (0.05% trypsin-EDTA, 2% SDS and 1% Triton X-100) and physical methods (electroporation and sonication). After decellularization, the content of DNA remaining in the tissue was quantitatively confirmed, and the structural change of the tissue and the retention and distribution of ECM components were evaluated through histological and histochemical analysis, respectively. Conditions of the chemical pretreatment that increase the efficiency of physical stimulation as well as decellularization, and conditions for electroporation and sonication without the use of detergents, unlike the methods performed in previous studies, were established to enable the complete decellularization of the skin tissue. The combinatorial decellularization treatment formed micropores in the lipid bilayers of the skin tissues while removing all cell and cellular residues without affecting the ECM properties. Therefore, this procedure can be widely used to fabricate bioscaffolds by decellularizing biological tissues with dense and complex structures.

Evaluating the validity of lightweight talar replacement designs: rational models and topologically optimized models.

BACKGROUND: Total talar replacement is normally stable and satisfactory. We studied a rational scaffold talus model for each size range created through topology optimization (TO) and comparatively evaluated a topologically optimized scaffold bone talus model using a finite element analysis (FEA). We hypothesized that the rational scaffold would be more effective for application to the actual model than the topologically optimized scaffold. METHODS: Size specification for the rational model was performed via TO and inner scaffold simplification. The load condition for worst-case selection reflected the peak point according to the ground reaction force tendency, and the load directions "plantar 10°" (P10), "dorsi 5°" (D5), and "dorsi 10°" (D10) were applied to select worst-case scenarios among the P10, D5, and D10 positions (total nine ranges) of respective size specifications. FEA was performed on each representative specification-standard model, reflecting a load of 5340 N. Among the small bone models selected as the worst-case, an arbitrary size was selected, and the validity of the standard model was evaluated. The standard model was applied to the rational structure during validity evaluation, and the TO model reflecting the internal structure derived by the TO of the arbitrary model was implemented. RESULT: In worst-case selection, the highest peak von Mises stress (PVMS) was calculated from the minimum D5 model (532.11 MPa). Thereafter, FEA revealed peak von Mises stress levels of 218.01 MPa and 565.35 MPa in the rational and topologically optimized models, respectively, confirming that the rational model yielded lower peak von Mises stress. The weight of the minimum model was reduced from 1106 g to 965.4 g after weight reduction through rational scaffold application. CONCLUSION: The rational inner-scaffold-design method is safer than topologically optimized scaffold design, and three types of rational scaffold, according to each size range, confirmed that all sizes of the talus within the anatomical dimension could be covered, which was a valid result in the total talar replacement design. Accordingly, we conclude that an implant design meeting the clinical design requirements, including patient customization, weight reduction, and mechanical stability, should be possible by applying a rational inner scaffold without performing TO design. The scaffold model weight was lower than that of the solid model, and the safety was also verified through FEA.

Diagnostic challenges and successful organ-preserving therapy in a case of secretory carcinoma of minor salivary glands.

BACKGROUND: Secretory carcinoma is a more recently described subtype of salivary gland carcinoma that may pose diagnostic challenges and frequently harbors NTRK fusions that may successfully be targeted by TRK inhibitors in advanced disease. CASE: We present the case of a female patient with secretory carcinoma arising in the base of tongue with persistent disease after debulking surgery and definitive chemoradiation. As an alternative to salvage surgery, which would have resulted in significant impairment of swallowing and speech function, a targeted therapy with the TRK-inhibitor larotrectinib against an identified ETV6-NTRK3 fusion product was initiated. Larotrectinib treatment has been well tolerated, resulted in durable complete response and the patient maintains good swallowing and speech function. CONCLUSION: The presented case underscores the importance of the accurate diagnosis of secretory carcinoma. It further highlights the impact of molecular testing as targeted therapies may play an important role in the management of advanced salivary gland cancers.

Pulsed Electrical Stimulation Enhances Consistency of Directional Migration of Adipose-Derived Stem Cells.

Electrical stimulation is a well-known strategy for regulating cell behavior, both in pathological and physiological processes such as wound healing, tissue regeneration, and embryonic development. Electrotaxis is the directional migration of cells toward the cathode or anode when subjected to electrical stimulation. In this study, we investigated the conditions for enhanced directional migration of electrically stimulated adipose-derived stem cells (ADSCs) during prolonged culture, using a customized agar-salt electrotaxis chamber. Exposure of ADSCs to a 1200 µA electric current for 3 h, followed by cessation of stimulation for 6 h and resumed stimulation for a further 3 h, increased directional cell migration toward the anode without inducing cell death. Moreover, Golgi polarization maintained the direction of polarity parallel to the direction of cell movement. Herein, we demonstrated that a pulsed electric current is sufficient to trigger directional migration of ADSCs in long-term culture while maintaining cell viability.

Optimal relative workload for managing low-injury risk in lower extremities of female field hockey players: A retrospective observational study.

ABSTRACT: Our study aimed to investigate the relative workload that is related to the injury in lower extremities of female field hockey players and to identify the optimal ratio of acute to chronic workloads (ACWR) depending on the playing position to manage low risk of sports-related injuries.Data were collected using a global positioning systems unit on a full-time basis and during competition among 52 players who were enrolled in Korea National Team. The ACWR was calculated by dividing the most recent 1 week workload by the prior 4 weeks workload. Injury risk was calculated for each category from very low to very high based on a z-score.In striker and midfielder, the injury risk was the lowest in the moderate-low category of total distance covered, meters per minute (MpM), repeated high-intensity effort bouts, and acceleration bouts, and the moderate-high category of high-intensity running distance (HID). The injury risk of a defender was the lowest in the moderate-low category of HID and MpM.The ACWR in total distance covered, MpM, repeated high-intensity effort bouts, and acceleration bouts should stay within the moderate-low category in striker and midfielder positions and HID and MpM in defender positions in order to manage low-risk of non-contact and soft tissue injuries in female field hockey players.

Tonsil-derived mesenchymal stem cells incorporated in reactive oxygen species-releasing hydrogel promote bone formation by increasing the translocation of cell surface GRP78.

Controlling the senescence of mesenchymal stem cells (MSCs) is essential for improving the efficacy of MSC-based therapies. Here, a model of MSC senescence was established by replicative subculture in tonsil-derived MSCs (TMSCs) using senescence-associated ß-galactosidase, telomere-length related genes, stemness, and mitochondrial metabolism. Using transcriptomic and proteomic analyses, we identified glucose-regulated protein 78 (GRP78) as a unique MSC senescence marker. With increasing cell passage number, GRP78 gradually translocated from the cell surface and cytosol to the (peri)nuclear region of TMSCs. A gelatin-based hydrogel releasing a sustained, low level of reactive oxygen species (ROS-hydrogel) was used to improve TMSC quiescence and self-renewal. TMSCs expressing cell surface-specific GRP78 (csGRP78+), collected by magnetic sorting, showed better stem cell function and higher mitochondrial metabolism than unsorted cells. Implantation of csGRP78+ cells embedded in ROS-hydrogel in rats with calvarial defects resulted in increased bone regeneration. Thus, csGRP78 is a promising biomarker of senescent TMSCs, and the combined use of csGRP78+ cells and ROS-hydrogel improved the regenerative capacity of TMSCs by regulating GRP78 translocation.