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Activation Inventor Professional 2011 Activation

Autodesk provides support to users of all of its current versions. If you opt to contact Autodesk for support, the available general support services include product activation, technical support, software updates, and hotfixes.

Three years ago, Autodesk announced its plan to end activation for outdated license versions. The phased approach instituted at that time was intended to provide users with well-defined support expectations. This is the last phase of that plan.

You can continue to use a previously installed and activated version, even if that version has reached end of support. If you have a perpetual license for a version that has reached end of support, you still have rights to use the license for as long as you want. However, if you are using an unsupported previous version, you will not be able to receive a new activation code to reactivate it on any device, for instance in case of a hardware failure. In addition to the potential downtime this might cause, security issues may arise because you will not be receiving software updates or hotfixes.

Autodesk no longer supports offline activation for 2021 products and earlier. If you have a perpetual license, activate your software by going online only once. After you activate online, you can continue to use 2021 software and earlier offline. This change doesn't apply to previous versions that you already activated offline; you can continue to use them as before.

However, for unsupported versions, you can't get a new activation code to reactivate that version for any device. We also do not release software updates or hotfixes for versions that have reached the end of support*.

In the context of artificial neural networks, the rectifier or ReLU (rectified linear unit) activation function[1][2] is an activation function defined as the positive part of its argument:

This activation function started showing up in the context of visual feature extraction in hierarchical neural networks starting in the late 1960s.[3][4] It was later argued that it has strong biological motivations and mathematical justifications.[5][6] In 2011 it was found to enable better training of deeper networks,[7] compared to the widely used activation functions prior to 2011, e.g., the logistic sigmoid (which is inspired by probability theory; see logistic regression) and its more practical[8] counterpart, the hyperbolic tangent. The rectifier is, as of 2017[update], the most popular activation function for deep neural networks.[9]

Rectifying activation functions were used to separate specific excitation and unspecific inhibition in the neural abstraction pyramid, which was trained in a supervised way to learn several computer vision tasks.[15] In 2011,[7] the use of the rectifier as a non-linearity has been shown to enable training deep supervised neural networks without requiring unsupervised pre-training. Rectified linear units, compared to sigmoid function or similar activation functions, allow faster and effective training of deep neural architectures on large and complex datasets.

The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents.

We find that combining αCTLA-4 and α4-1BB antibodies in the context of a Flt3-ligand, but not a GM-CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T-cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T-cells. Anti-4-1BB also depressed regulatory T-cell infiltration of tumors. 4-1BB activation strongly stimulated inflammatory cytokine production in the vaccine and tumor draining lymph nodes and in the tumor itself. The addition of CTLA-4 blockade further increased IFN-γ production from CD4+ effector T-cells in the vaccine draining node and the tumor. Anti 4-1BB treatment, with or without CTLA-4 blockade, induced approximately 75% of CD8+ and 45% of CD4+ effector T-cells in the tumor to express the killer cell lectin-like receptor G1 (KLRG1). Tumors treated with combination antibody therapy showed 1.7-fold greater infiltration by these KLRG1+CD4+ effector T-cells than did those treated with α4-1BB alone.

The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is induced on T-cells shortly after activation and functions to attenuate their proliferation, IL-2 production, and contact time with antigen presenting cells (APC) [1], [2]. Also, CTLA-4 appears to support the function of the regulatory T-cell (Treg) compartment [3]. Antibody blockade of CTLA-4 removes these suppressive signals and allows tumor-specific T-cells which would otherwise be anergized to expand and continue to perform effector functions. Previously, we have shown that the therapeutic efficacy of CTLA-4 blockade against poorly immunogenic tumors like B16 melanoma is strongly enhanced by co-administration of an autologous tumor vaccine expressing either the cytokine Granulocyte-macrophage colony-stimulating factor (GM-CSF) or FMS-like tyrosine kinase 3 ligand (Flt3-ligand) [4], [5].

4-1BB (CD137) belongs to the Tumor Necrosis Factor Receptor (TNFR) superfamily and is transiently upregulated on both CD4+ and CD8+ T-cells following activation [6]. 4-1BB ligation is known to co-stimulate CD8+ T-cells increasing their proliferation, TH1 cytokine production, and survival [7]. A majority of Tregs express 4-1BB, but it remains unclear whether agonist antibody treatment exerts a pro- or anti-suppressive effect on these cells [8], [9], [10], [11]. In immunotherapy studies, 4-1BB antibodies can enhance tumor rejection, increase tumor-specific cytotoxicity, and may render effector T-cells resistant to Treg suppression [10], [12], [13], [14], [15]. The mechanisms underlying many of these observed anti-tumor effects, however, remain to be elucidated.

Prior studies have shown that agonistic 4-1BB antibodies with or without CTLA-4 blockade can promote the rejection of some murine tumors and ameliorate auto-immune toxicity; however, poorly immunogenic tumors such as B16 melanoma do not respond to antibody therapy alone [10], [14]. We hypothesized that increasing the tumor-specific T-cell frequency through vaccination would allow us to better observe the interaction between 4-1BB activation and CTLA-4 blockade in the B16 melanoma system.

By combining T-cell co-inhibitory blockade with co-stimulatory activation, we were able to induce rejection of poorly immunogenic B16 melanoma tumors. Also, we have characterized the cellular and molecular mechanisms driving this response further clarifying the basic processes necessary to achieve immune-mediated tumor rejection.

To understand the apparent synergy between CTLA-4 blockade and 4-1BB activation in the context of our Flt3-ligand base vaccine, we sought to dissect the effects of each therapy on T-cell infiltration of tumor in this background. 4-1BB activation promoted very strong CD8 infiltration of B16 melanoma, but in doing so depressed the relative fraction of CD4+ effector cells (Figure 2A and B). In terms of absolute T-cell numbers, the CD8 T-cell density increased while the CD4 effector T-