Development and pilot testing of HEXORR: Hand EXOskeleton Rehabilitation Robot

<p>Abstract</p> <p>Background</p> <p>Following acute therapeutic interventions, the majority of stroke survivors are left with a poorly functioning hemiparetic hand. Rehabilitation robotics has shown promise in providing patients with intensive therapy leading to functional gains. Because of the hand's crucial role in performing activities of daily living, attention to hand therapy has recently increased.</p> <p>Methods</p> <p>This paper introduces a newly developed Hand Exoskeleton Rehabilitation Robot (HEXORR). This device has been designed to provide full range of motion (ROM) for all of the hand's digits. The thumb actuator allows for variable thumb plane of motion to incorporate different degrees of extension/flexion and abduction/adduction. Compensation algorithms have been developed to improve the exoskeleton's backdrivability by counteracting gravity, stiction and kinetic friction. We have also designed a force assistance mode that provides extension assistance based on each individual's needs. A pilot study was conducted on 9 unimpaired and 5 chronic stroke subjects to investigate the device's ability to allow physiologically accurate hand movements throughout the full ROM. The study also tested the efficacy of the force assistance mode with the goal of increasing stroke subjects' active ROM while still requiring active extension torque on the part of the subject.</p> <p>Results</p> <p>For 12 of the hand digits'15 joints in neurologically normal subjects, there were no significant ROM differences (P > 0.05) between active movements performed inside and outside of HEXORR. Interjoint coordination was examined in the 1^stand 3^rddigits, and no differences were found between inside and outside of the device (P > 0.05). Stroke subjects were capable of performing free hand movements inside of the exoskeleton and the force assistance mode was successful in increasing active ROM by 43 ± 5% (P < 0.001) and 24 ± 6% (P = 0.041) for the fingers and thumb, respectively.</p> <p>Conclusions</p> <p>Our pilot study shows that this device is capable of moving the hand's digits through nearly the entire ROM with physiologically accurate trajectories. Stroke subjects received the device intervention well and device impedance was minimized so that subjects could freely extend and flex their digits inside of HEXORR. Our active force-assisted condition was successful in increasing the subjects' ROM while promoting active participation.</p

Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia

<p>Abstract</p> <p>Background</p> <p>Recent evidence suggests that CD4⁺CD25⁺FoxP3⁺regulatory T-cells (Treg) may be responsible for the failure of host anti-tumour immunity by suppressing cytotoxic T- cells. We assessed the prognostic significance of tumour infiltrating lymphocytes (TIL) in intestinal-type gastric cardiac cancer.</p> <p>Methods</p> <p>Tumour infiltrating lymphocyte (TIL) subsets and tumour infiltrating macrophages (TIM) were investigated in 52 cases using tissue microarrays. The interrelationship between the cell populations (CD3+, CD8+, CD20+, CD68+, GranzymeB+, FoxP3+) in different compartments and NED-survival was investigated (median follow-up time: 61 months).</p> <p>Results</p> <p>Intraepithelial infiltration with TIL and TIM including Treg was generally low and not related to NED-survival. However, patients with large numbers of FoxP3⁺Treg in the tumour stroma (>125.9 FoxP3⁺TILs/mm²) had a median survival time of 58 months while those with low FoxP3⁺TIL counts (<125.9 FoxP3⁺TILs/mm²) had a median survival time of 32 months (p = 0.006). Patients with high versus low stromal CD68⁺/FoxP3⁺cell ratios in primary tumour displayed median survivals of 32 and 55 months, respectively (p = 0.008).</p> <p>Conclusion</p> <p>Our results suggest that inflammatory processes within the tumour stroma of gastric intestinal-type adenocarcinomas located at the gastric cardia may affect outcome in two ways. Tumour-infiltrating macrophages are likely to promote carcinogenesis while large numbers of Treg are associated with improved outcome probably by inhibiting local inflammatory processes promoting carcinogenesis. Thus, inhibition of Treg may not be a feasible treatment option in gastric adenocarcinoma.</p

Evaluating the Cellular Targets of Anti-4-1BB Agonist Antibody during Immunotherapy of a Pre-Established Tumor in Mice

Manipulation of the immune system represents a promising avenue for cancer therapy. Rational advances in immunotherapy of cancer will require an understanding of the precise correlates of protection. Agonistic antibodies against the tumor necrosis factor receptor family member 4-1BB are emerging as a promising tool in cancer therapy, with evidence that these antibodies expand both T cells as well as innate immune cells. Depletion studies have suggested that several cell types can play a role in these immunotherapeutic regimens, but do not reveal which cells must directly receive the 4-1BB signals for effective therapy.We show that re-activated memory T cells are superior to resting memory T cells in control of an 8-day pre-established E.G7 tumor in mice. We find that ex vivo activation of the memory T cells allows the activated effectors to continue to divide and enter the tumor, regardless of antigen-specificity; however, only antigen-specific reactivated memory T cells show any efficacy in tumor control. When agonistic anti-4-1BB antibody is combined with this optimized adoptive T cell therapy, 80% of mice survive and are fully protected from tumor rechallenge. Using 4-1BB-deficient mice and mixed bone marrow chimeras, we find that it is sufficient to have 4-1BB only on the endogenous host alphabeta T cells or only on the transferred T cells for the effects of anti-4-1BB to be realized. Conversely, although multiple immune cell types express 4-1BB and both T cells and APC expand during anti-4-1BB therapy, 4-1BB on cells other than alphabeta T cells is neither necessary nor sufficient for the effect of anti-4-1BB in this adoptive immunotherapy model.This study establishes alphabeta T cells rather than innate immune cells as the critical target in anti-4-1BB therapy of a pre-established tumor. The study also demonstrates that ex vivo activation of memory T cells prior to infusion allows antigen-specific tumor control without the need for reactivation of the memory T cells in the tumor

The Role of Regulatory T Cells in Cancer

There has been an explosion of literature focusing on the role of regulatory T (Treg) cells in cancer immunity. It is becoming increasingly clear that Treg cells play an active and significant role in the progression of cancer, and have an important role in suppressing tumor-specific immunity. Thus, there is a clear rationale for developing clinical strategies to diminish their regulatory influences, with the ultimate goal of augmenting antitimor immunity. Therefore, manipulation of Treg cells represent new strategies for cancer treatment. In this Review, I will summarize and review the explosive recent studies demonstrating that Treg cells are increased in patients with malignancies and restoration of antitumor immunity in mice and humans by depletion or reduction of Treg cells. In addition, I will discuss both the prognostic value of Treg cells in tumor progression in tumor-bearing hosts and the rationale for strategies for therapeutic vaccination and immunotherapeutic targeting of Treg cells with drugs and microRNA