Effects of vestibular stimulation on gait stability when walking at different step widths.

Vestibular information modulates muscle activity during gait, presumably to contribute to stability. If this is the case, stronger effects of perturbing vestibular information on local dynamic stability of gait, a measure of the locomotor system's response to small, naturally occurring perturbations, can be expected for narrow-base walking (which needs more control) than for normal walking and smaller effects for wide-base walking (which needs less control). An important mechanism to stabilize gait is to coordinate foot placement to center of mass (CoM) state. Vestibular information most likely contributes to sensing this CoM state. We, therefore, expected that stochastic electrical vestibular stimulation (EVS) would decrease the correlation between foot placement and CoM state during the preceding swing phase. In 14 healthy participants, we measured the kinematics of the trunk (as a proxy of the CoM), and feet, while they walked on a treadmill in six conditions: control (usual step width), narrow-base, and wide-base, each with and without stochastic EVS (peak amplitude of 5 mA; RMS of ~ 1.2 mA; frequency band from 0 to 25 Hz). Stochastic EVS decreased local dynamic stability irrespective of step width. Foot placement correlated stronger with trunk motion during walking with EVS than without in the control condition. However, residual variance in foot placement was increased when walking with EVS, indicating less precise foot placement. Thus, a vestibular error signal leads to a decrease in gait stability and precision of foot placement, but these effects are not consistently modulated by step width.

Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.

In-vitro phagocytosis and intracellular killing of Pasteurella multocida B:2 by phagocytic cells of buffaloes.

Pasteurella multocida B:2 is a Gram-negative organism causing haemorrhagic septicaemia (HS) in buffaloes. It causes severe pulmonary infection, leading to infiltration of numerous macrophages and neutrophils. Despite the inflammatory response, buffaloes succumb to HS. This study aims to evaluate the in-vitro efficacy of macrophages and neutrophils of buffalo following exposure to P. multocida B:2. In-vitro infections were done using 107 cfu/ml of P. multocida B:2 for Group 1, Escherichia coli for Group 2 and Mannhaemia haemolytica A:2 for Group 3 cells. The inoculated cell cultures were harvested at 0, 30, 60 and 120 min post-exposure and the phagocytic, killing and cell death rates were determined. Both phagocytosis and killing rates of all bacteria increased over time. Phagocytosis involved between 71% and 73% neutrophils and between 60% and 64% macrophages at 120 min. Killing rate of all bacteria involved between 76% and 79% for neutrophils and between 70% and 74% for macrophages at 120 min. Death rate of neutrophils ranged between 67% in Group 3, and 88% in Group 1 at 120 min, significantly (p < 0.05) higher than Group 3 but insignificant (p > 0.05) than Group 2. Similar pattern was observed for death rate of macrophages. The phagocytosis and killing rates of P. multocida B:2 were similar to other bacterial species used in this study but more neutrophils and macrophages were dead following infection by P. multocida B:2 than M. haemolytica A:2.

Risk factors for keratinocyte carcinoma skin cancer in nonwhite individuals: A retrospective analysis.

BACKGROUND: Because most of the US population will consist of nonwhite individuals by the year 2043, it is essential that both physicians and patients are educated about skin cancer in nonwhite persons. OBJECTIVE: To update the epidemiology, investigate specific risk factors, and facilitate earlier diagnosis and intervention of keratinocyte carcinoma in nonwhite individuals. METHODS: Institutional review board-approved retrospective chart review of all nonwhite patients who had received a biopsy-proven diagnosis of skin cancer at Drexel Dermatology during June 2008-June 2015. RESULTS: Squamous cell carcinoma (SCC) was the most commonly diagnosed skin cancer in black and Asian populations, and basal cell carcinoma was the most common skin cancer in Hispanics. Black persons exhibited the majority of their SCC lesions in sun-protected areas, particularly the anogenital area. On average, current smokers received skin cancer diagnoses 12.27 years earlier than former smokers and 9.36 years earlier than nonsmokers. LIMITATIONS: Single-center design and interpractitioner variability of skin examination. CONCLUSION: The importance of lesions in photoprotected areas in nonwhite individuals should not go overlooked. However, emphasis should also be placed on active examination of sun-protected areas in nonwhite persons and recognition of the relationship between human papillomavirus and genital SCC lesions. Smoking cessation should be integrated in dermatologic counseling of all patients. Interventions tailored to each of these ethnic groups are needed.

Prebiotic potential of Agave angustifolia Haw fructans with different degrees of polymerization.

Inulin-type fructans are the most studied prebiotic compounds because of their broad range of health benefits. In particular, plants of the Agave genus are rich in fructans. Agave-derived fructans have a branched structure with both ß-(2→1) and ß-(2→6) linked fructosyl chains attached to the sucrose start unit with a degree of polymerization (DP) of up to 80 fructose units. The objective of this work was to assess the prebiotic potential of three Agave angustifolia Haw fructan fractions (AFF) with different degrees of polymerization. The three fructan fractions were extracted from the agave stem by lixiviation and then purified by ultrafiltration and ion exchange chromatography: AFF1, AFF2 and AFF3 with high (3-60 fructose units), medium (2-40) and low (2-22) DP, respectively. The fructan profile was determined with high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD), which confirmed a branched fructan structure. Structural elucidation was performed by Fourier Transform Infra-Red Spectroscopy. The AFF spectrum shows characteristic fructan bands. The prebiotic effect of these fractions was assessed in vitro through fermentation by Bifidobacterium and Lactobacillus strains. Four growth patterns were observed. Some bacteria did not grow with any of the AFF, while other strains grew with only AFF3. Some bacteria grew according to the molecular weight of the AFF and some grew indistinctly with the three fructan fractions.

Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies.

Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2M is expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitro and in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.

Assessment of daily and weekly fatigue among African American cancer survivors.

This investigation evaluates two common measures of cancer-related fatigue, one multidimensional/retrospective and one unidimensional/same day. Fifty-two African American survivors of diverse cancers completed fatigue visual analogue scales once daily, and the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) once weekly, for four weeks. Zero-order correlations showed retrospective fatigue was significantly related to average, peak, and most recent same-day fatigue. Multilevel random coefficient modeling showed unidimensional fatigue shared the most variance with the MFSI-SF's General subscale for three weeks, and with the Vigor subscale for one week. Researchers and clinicians may wish to prioritize multidimensional measures when assessing cancer-related fatigue, if appropriate.

Design of magnetorheological brake for forearm rotation of a wrist prosthesis.

A wrist joint in upper limb prostheses significantly increases its handling capacity. However, current prostheses cannot reproduce the ability of torque combined with the volume and weight of the human wrist. Consequently, they do not provide high efficiency in handling and generate user dissatisfaction. In this context, this study aims to optimal design a wrist supination and pronation brake to improve the handling capacity of an upper limb prosthesis. The wrist actuator consists of an EC motor and harmonic drive parallel with a magnetorheological brake. The brake guarantees a fast response time, low energy consumption, controllability, and small dimensions. A particle swarm algorithm is applied to optimize design variables to minimize mass and energy consumption. As a result, the brake provided resistive torque of 7.4 N.m with dimensions close to a healthy member and weighing 0.1972 kg. Finally, a finite element analysis confirmed a satisfactory magnetic flux for the magnetorheological brake operating conditions. The designed brake addressed all the desired characteristics and is suitable to integrate the forearm prosthesis with wrist rotation.

Stabilization demands of walking modulate the vestibular contributions to gait.

Stable walking relies critically on motor responses to signals of head motion provided by the vestibular system, which are phase-dependent and modulated differently within each muscle. It is unclear, however, whether these vestibular contributions also vary according to the stability of the walking task. Here we investigate how vestibular signals influence muscles relevant for gait stability (medial gastrocnemius, gluteus medius and erector spinae)-as well as their net effect on ground reaction forces-while humans walked normally, with mediolateral stabilization, wide and narrow steps. We estimated local dynamic stability of trunk kinematics together with coherence of electrical vestibular stimulation (EVS) with muscle activity and mediolateral ground reaction forces. Walking with external stabilization increased local dynamic stability and decreased coherence between EVS and all muscles/forces compared to normal walking. Wide-base walking also decreased vestibulomotor coherence, though local dynamic stability did not differ. Conversely, narrow-base walking increased local dynamic stability, but produced muscle-specific increases and decreases in coherence that resulted in a net increase in vestibulomotor coherence with ground reaction forces. Overall, our results show that while vestibular contributions may vary with gait stability, they more critically depend on the stabilization demands (i.e. control effort) needed to maintain a stable walking pattern.

Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators.

BACKGROUND: Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. METHODS: To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing. RESULTS: Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration. CONCLUSIONS: Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.

Applying Antibodies Inside Cells: Principles and Recent Advances in Neurobiology, Virology and Oncology.

To interfere with cell function, many scientists rely on methods that target DNA or RNA due to the ease with which they can be applied. Proteins are usually the final executors of function but are targeted only indirectly by these methods. Recent advances in targeted degradation of proteins based on proteolysis-targeting chimaeras (PROTACs), ubiquibodies, deGradFP (degrade Green Fluorescent Protein) and other approaches have demonstrated the potential of interfering directly at the protein level for research and therapy. Proteins can be targeted directly and very specifically by antibodies, but using antibodies inside cells has so far been considered to be challenging. However, it is possible to deliver antibodies or other proteins into the cytosol using standard laboratory equipment. Physical methods such as electroporation have been demonstrated to be efficient and validated thoroughly over time. The expression of intracellular antibodies (intrabodies) inside cells is another way to interfere with intracellular targets at the protein level. Methodological strategies to target the inside of cells with antibodies, including delivered antibodies and expressed antibodies, as well as applications in the research areas of neurobiology, viral infections and oncology, are reviewed here. Antibodies have already been used to interfere with a wide range of intracellular targets. Disease-related targets included proteins associated with neurodegenerative diseases such as Parkinson's disease (α-synuclein), Alzheimer's disease (amyloid-ß) or Huntington's disease (mutant huntingtin [mHtt]). The applications of intrabodies in the context of viral infections include targeting proteins associated with HIV (e.g. HIV1-TAT, Rev, Vif, gp41, gp120, gp160) and different oncoviruses such as human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein-Barr virus, and they have been used to interfere with various targets related to different processes in cancer, including oncogenic pathways, proliferation, cell cycle, apoptosis, metastasis, angiogenesis or neo-antigens (e.g. p53, human epidermal growth factor receptor-2 [HER2], signal transducer and activator of transcription 3 [STAT3], RAS-related RHO-GTPase B (RHOB), cortactin, vascular endothelial growth factor receptor 2 [VEGFR2], Ras, Bcr-Abl). Interfering at the protein level allows questions to be addressed that may remain unanswered using alternative methods. This review addresses why direct targeting of proteins allows unique insights, what is currently feasible in vitro, and how this relates to potential therapeutic applications.

Head orientation and gait stability in young adults, dancers and older adults.

BACKGROUND: Control of body orientation requires head motion detection by the vestibular system and small changes with respect to the gravitational acceleration vector could cause destabilization. RESEARCH QUESTION: We aimed to compare the effects of different head orientations on gait stability in young adults, dancers and older adults. METHODS: Three groups of 10 subjects were evaluated, the first composed of young adults (aged 18-30 years), the second composed of young healthy dancers under high performance dance training (aged 18-30 years), and the third group composed of community-dwelling older adults (aged 65-80 years). Participants walked on a treadmill at their preferred speed in four distinct head orientation conditions for four minutes each: control (neutral orientation); dynamic yaw (following a target over 45° bilaterally); up (15° neck extension), and down (40° neck flexion). Foot and trunk kinematic data were acquired using a 3D motion capture system and the gait pattern was assessed by basic gait parameters (step length, stride width and corresponding variability) and gait stability (local divergence exponents and margins of stability). Main effects of conditions and groups, as well as their interaction effects, were evaluated by repeated-measures analysis of variance. RESULTS: Interactions of group and head orientation were found for both step length and stride width variability; main effects of head orientation were found for all evaluated parameters and main effects of group were found for step length and its variability and local divergence exponents in all directions. SIGNIFICANCE: As expected, the older adults group showed less stable gait (higher local divergence exponent), the shortest step length and greater step length variability. However, contrary to expectation, the dancers were not more stable. The yaw condition was the most challenging for all groups and the down condition seemed to be least challenging.

Infusing global and intercultural perspectives to transform school psychology and school psychologists.

School psychology has been criticized for limited attention to and limited evidence-based resources for diverse populations in domestic and international settings, in part because of its foundations on psychological knowledge generated primarily in North America and Western Europe. Moreover, in the past 25 years, the profession has made insufficient progress in changing its focus toward an ecological systems perspective as initially envisioned by Conoley and Gutkin in 1995 and revisited in this issue. In this article, we embrace and expand that vision to include the infusion of global and intercultural perspectives into school psychology research, training, practice, policy, and advocacy as a means to address cultural diversity within local contexts across the globe, with a particular focus on school psychology within the United States. We begin with a discussion of terminology that addresses international and cross-cultural issues related to diversity. We then examine past and present perspectives and approaches to cultural diversity and globalization within school psychology and propose future directions for research, training, practice, policy, and advocacy within a global-intercultural perspective. We conclude with our reflections about transforming school psychology and school psychologists. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Asthma 1-2-3: a low literacy multimedia tool to educate African American adults about asthma.

Asthma 1-2-3 is a newly-developed low-literacy multimedia education tool designed to promote asthma self-care concepts among African American adults. An expert panel (n = 10) informed content development for the tool. The video script and storyboard imagery were shown to 30 African Americans recruited from the American Lung Association, whose reactions and comments guided further revisions. The final version was pilot tested in three diverse community settings in Chicago to determine the efficacy of Asthma 1-2-3 at improving patient understanding of asthma and its symptoms. In all, 130 adults participated in the pilot test. Knowledge scores significantly improved from pretest to posttest following presentation of the developed tool for subjects across all literacy levels (Pretest: Mean = 4.2 [SD = 1.6]; Posttest: M = 6.8 [SD = 2.0], P < 0.001). Symptom pathophysiology concepts were the least understood. Individuals with low literacy had less total knowledge score gains compared to those with marginal and adequate literacy (1.8, 2.6, and 3.2 respectively; P = 0.002). The multimedia tool significantly improved understanding of asthma. Individuals with limited literacy may require additional instruction, repeated viewing, or added tangible cues (i.e. supplementary print materials) to support knowledge retention. In general, feedback from the target population was particularly helpful in the development of the tool and its initial evaluation, and should be considered as a necessary step in the creation of other patient education materials.

Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kß Inhibition in PTEN Loss Melanoma.

PURPOSE: OX40 agonist-based combinations are emerging as a novel avenue to improve the effectiveness of cancer immunotherapy. To better guide its clinical development, we characterized the role of the OX40 pathway in tumor-reactive immune cells. We also evaluated combining OX40 agonists with targeted therapy to combat resistance to cancer immunotherapy.Experimental Design: We utilized patient-derived tumor-infiltrating lymphocytes (TILs) and multiple preclinical models to determine the direct effect of anti-OX40 agonistic antibodies on tumor-reactive CD8+ T cells. We also evaluated the antitumor activity of an anti-OX40 antibody plus PI3Kß inhibition in a transgenic murine melanoma model (Braf mutant, PTEN null), which spontaneously develops immunotherapy-resistant melanomas. RESULTS: We observed elevated expression of OX40 in tumor-reactive CD8+ TILs upon encountering tumors; activation of OX40 signaling enhanced their cytotoxic function. OX40 agonist antibody improved the antitumor activity of CD8+ T cells and the generation of tumor-specific T-cell memory in vivo. Furthermore, combining anti-OX40 with GSK2636771, a PI3Kß-selective inhibitor, delayed tumor growth and extended the survival of mice with PTEN-null melanomas. This combination treatment did not increase the number of TILs, but it instead significantly enhanced proliferation of CD8+ TILs and elevated the serum levels of CCL4, CXCL10, and IFNγ, which are mainly produced by memory and/or effector T cells. CONCLUSIONS: These results highlight a critical role of OX40 activation in potentiating the effector function of tumor-reactive CD8+ T cells and suggest further evaluation of OX40 agonist-based combinations in patients with immune-resistant tumors.

Molecular signature detection of circulating tumor cells using a panel of selected genes.

Circulating tumor cell (CTC) detection in peripheral blood of colon and other epithelial cancer patients is becoming a scientifically recognised indicator for the presence of primary tumors and/or metastasis. The resulting need to further develop CTC detection-based systems for improved diagnosis, prognosis and assessment of therapy efficacy in tumour patients has prompted the application of different approaches, including expression analysis of tissue-specific and epithelial genes. In this context, lack of specificity of the analysed genes remains a fundamental problem for reliable CTC detection. In this study, we have selected a panel of highly specific epithelial genes: cytokeratin 20 (CK20), cytokeratin 19 (CK19), carcinoembryonic antigen (CEA) and guanylyl cyclase C (GCC), and performed RT-PCR analysis to assess their expression in total blood and in different cell fractions of peripheral blood (PBMC and CD45-negative population) of cancer patients and healthy controls. Our results demonstrate that analysis of a single gene in a CTC-enriched population (CD45(-) peripheral blood cells) of cancer patients allows detection of a CTC molecular signature in at most 63.3% of cases, while analysis of all four genes performed in all three sample types increases the detection of positive patient samples to 87.7%. Healthy controls did not show positivity for any combination of these genes, although positivity was observed for the CEA marker alone, which was detected in 3 (6.6%) out of 45 donors, and only in the CD45(-) fraction. Here, we demonstrate that combined analysis of the genes above, in multiple blood fractions, results in a highly specific and sensitive CTC detection system in patients with metastatic solid tumors. Therefore, we believe that validation on a large scale of this approach, which demonstrates higher specificity in patients compared to controls, could become a relevant CTC screening test in patients with established metastatic disease, and furthermore, may also be useful for evaluating the possible presence of CTCs before the onset of clinically manifested metastatic spreading.

Mohs micrographic surgery for digital melanoma and nonmelanoma skin cancers.

Treatment of digital skin cancers is challenging due to various functional and cosmetic implications. Traditionally, routine treatment includes radical amputation, but digital skin cancers are increasingly being treated with more conservative, tissue-sparing methods such as Mohs micrographic surgery (MMS), which provides excellent tissue conservation and margin control when used to treat melanoma and nonmelanoma skin cancers (NMSCs). In this study, we conducted a retrospective chart review to evaluate clinical outcomes following MMS for treatment of digital melanoma and NMSCs.

Psoriasis, chronic tonsillitis, and biofilms: Tonsillar pathologic findings supporting a microbial hypothesis.

Group A Streptococcus has been identified as a possible etiologic agent in psoriasis in epidemiologic, immunologic, immunopathologic, medical, and surgical studies. Tonsillectomy has been shown to provide considerable relief to 75% of patients with plaque psoriasis. Even with the substantial evidence supporting group A Streptococcus as a causative pathogen in psoriasis, it is an elusive pathogen because it is not culturable, nor does it exhibit any positive serologic evidence of its presence. One possible reason for the negative cultures and negative serology findings with group A Streptococcus is the development of biofilms. We conducted a pathologic study to determine whether biofilms were present in the tonsillar tissues of 10 patients with psoriasis-6 men and 4 women, aged 25 to 64 years (mean: 48)-and in 10 age- and sex-matched controls with chronic tonsillitis who did not have psoriasis. We found that biofilms were present in every tonsillectomy specimen we examined, including those of the controls. Whereas psoriasis has been considered a "double hit" phenomenon, we believe that the development of skin lesions is likely attributable to the presence of the gene PSORS together with the biofilm in psoriasis patients rather than to the biofilm itself. Biofilms have been identified in both extra- and intracellular locations. We believe our findings add further evidence supporting a microbial pathogenesis of this disease.

Could Activity Modifications Indicate Physical Decline Among Adults With Symptomatic Knee Osteoarthritis?

OBJECTIVES: Mobility activity modifications indicate early functional losses that act as precursors to future declines among community-dwelling older adults. However, there is scarce evidence on whether activity modifications indicate poorer physical health among adults with symptomatic osteoarthritis, a major cause of disability. Our purpose was to investigate whether patient-reported mobility activity modifications indicated poorer physical health among adults with symptomatic knee osteoarthritis. DESIGN: Secondary cross-sectional analysis of randomized trial data was performed. Preclinical Disability Questionnaire was used to group participants into the following three categories: difficulty, modified, and no difficulty walking/stair climbing. Kruskal Wallis and χ tests were used to compare clinical factors across groups. RESULTS: Among 121 participants (median age = 60 yrs; 73% female; 60% white), less than 10% had modified walking/stair climbing. Compared with those with no walking difficulty, participants with modified walking had significantly less balance (P = 0.01) and global health (P = 0.01) as well as greater knee pain (P = 0.05) and physical disability (P = 0.04). Those with modified stair climbing had significantly smaller walking distances (P = 0.03) compared with those with no difficulty stair climbing. CONCLUSIONS: Activity modifications may signal early impairments in physical health among people with symptomatic knee osteoarthritis. If confirmed, patient-reported activity modifications may enhance symptom evaluation in osteoarthritis and enable a better understanding of the disablement process.

The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy.

Background: Immunotherapy has increasingly become a staple in cancer treatment. However, substantial limitations in the durability of response highlight the need for more rational therapeutic combinations. The aim of this study is to investigate how to make tumor cells more sensitive to T-cell-based cancer immunotherapy. Methods: Two pairs of melanoma patient-derived tumor cell lines and their autologous tumor-infiltrating lymphocytes were utilized in a high-throughput screen of 850 compounds to identify bioactive agents that could be used in combinatorial strategies to improve T-cell-mediated killing of tumor cells. RNAi, overexpression, and gene expression analyses were utilized to identify the mechanism underlying the effect of Topoisomerase I (Top1) inhibitors on T-cell-mediated killing. Using a syngeneic mouse model (n = 5 per group), the antitumor efficacy of the combination of a clinically relevant Top1 inhibitor, liposomal irinotecan (MM-398), with immune checkpoint inhibitors was also assessed. All statistical tests were two-sided. Results: We found that Top1 inhibitors increased the sensitivity of patient-derived melanoma cell lines (n = 7) to T-cell-mediated cytotoxicity (P < .001, Dunnett's test). This enhancement is mediated by TP53INP1, whose overexpression increased the susceptibility of melanoma cell lines to T-cell cytotoxicity (2549 cell line: P = .009, unpaired t test), whereas its knockdown impeded T-cell killing of Top1 inhibitor-treated melanoma cells (2549 cell line: P < .001, unpaired t test). In vivo, greater tumor control was achieved with MM-398 in combination with α-PD-L1 or α-PD1 (P < .001, Tukey's test). Prolonged survival was also observed in tumor-bearing mice treated with MM-398 in combination with α-PD-L1 (P = .002, log-rank test) or α-PD1 (P = .008, log-rank test). Conclusions: We demonstrated that Top1 inhibitors can improve the antitumor efficacy of cancer immunotherapy, thus providing the basis for developing novel strategies using Top1 inhibitors to augment the efficacy of immunotherapy.