METHODS FOR TREATING CANCER BY ADJUSTING SELECTED METABOLITES

Abstract

Cancer treatment methods that include adjusting the concentration of selected metabolites in a blood supply to yield a perfusate with metabolite concentrations that promote terminal cellular differentiation in a tumor and delivering the perfusate to an artery of a patient. In some examples, the methods include adjusting the concentration of glycerol in a blood supply to yield a perfusate with reduced osmotic pressure, adjusting the concentration of ascorbic acid in the perfusate to maintain a selected redox potential, adjusting the concentration of glutamine in the perfusate to downregulate histone deacetylases, adjusting the concentration of butyrate in the perfusate to signal starvation, and delivering the perfusate to an artery of a patient, wherein the concentrations of glycerol, ascorbic acid, glutamine, and butyrate are selected to promote terminal cellular differentiation in a tumor.

Claims

1. A method for treating cancer comprising: adjusting the concentration of selected metabolites in a blood supply to yield a perfusate with metabolite concentrations that promote terminal cellular differentiation in a tumor; and delivering the perfusate to an artery of a patient.

2. The method of claim 1, wherein the concentration of selected metabolites in a blood supply are adjusted to reduce the osmotic pressure of the perfusate.

3. The method of claim 2, wherein adjusting the concentration of selected metabolites in a blood supply includes adjusting the concentration of glycerol to reduce the osmotic pressure of the perfusate.

4. The method of claim 4, wherein adjusting the concentration of selected metabolites in a blood supply includes increasing the concentration of glycerol in the perfusate.

5. The method of claim 1, wherein adjusting the concentration of selected metabolites in a blood supply includes maintaining a selected redox potential of the perfusate.

6. The method of claim 5, wherein the selected redox potential corresponds to a selected concentration of intra-cellular glutathione that promotes apoptosis in a tumor.

7. The method of claim 6, wherein the selected redox potential of the perfusate is maintained by adjusting the concentration of ascorbic acid in the perfusate.

8. The method of claim 1, wherein adjusting the concentration of selected metabolites in a blood supply includes adjusting the concentration of glutamine in the perfusate to downregulate histone deacetylases.

9. The method of claim 8, wherein adjusting the concentration of selected metabolites in a blood supply includes reducing the concentration of glutamine in the perfusate.

10. The method of claim 9, wherein adjusting the concentration of selected metabolites in a blood supply includes reducing the concentration of glutamine in the perfusate to a concentration selected to reduce cysteine exporting from a tumor cell.

11. The method of claim 1, wherein adjusting the concentration of selected metabolites in a blood supply includes adjusting the concentration of selected metabolites in the perfusate to signal starvation.

12. The method of claim 11, wherein adjusting the concentration of selected metabolites in a blood supply includes adjusting the concentration of butyrate in the perfusate to signal starvation.

13. The method of claim 12, wherein adjusting the concentration of butyrate in the perfusate to signal starvation includes increasing the concentration of butyrate in the perfusate.

14. The method of claim 11, wherein adjusting the concentration of selected metabolites in a blood supply includes adjusting the concentration of ketone bodies in the perfusate to signal starvation.

15. The method of claim 14, wherein adjusting the concentration of ketone bodies in the perfusate to signal starvation includes increasing the concentration of ketone bodies in the perfusate.

16. The method of claim 1, wherein the concentration of selected metabolites in a blood supply are adjusted to concentrations selected to regulate expression of the Yamanaka stem cell factors in the perfusate.

17. The method of claim 1, wherein the concentration of selected metabolites in a blood supply are adjusted to concentrations selected to restore a patient's compromised immune response to a tumor to a baseline immune response.

18. The method of claim 17, wherein the concentration of selected metabolites in a blood supply are adjusted to concentrations selected to restore extracellular oxidation reduction potential in an environment proximate a tumor to within a baseline range of extracellular oxidation reduction potential.

19. A method for treating cancer comprising: adjusting the concentration of glycerol in a blood supply to yield a perfusate with reduced osmotic pressure; adjusting the concentration of ascorbic acid in the perfusate to maintain a selected redox potential; adjusting the concentration of glutamine in the perfusate to downregulate histone deacetylases; adjusting the concentration of butyrate in the perfusate to signal starvation; and delivering the perfusate to an artery of a patient; wherein the concentrations of glycerol, ascorbic acid, glutamine, and butyrate are selected to promote terminal cellular differentiation in a tumor.

20. The method of claim 19, wherein: adjusting the concentration of glycerol in a blood supply to yield a perfusate with reduced osmotic pressure includes increasing the concentration of glycerol; adjusting the concentration of ascorbic acid in the perfusate to maintain a selected redox potential includes increasing the concentration of ascorbic acid; adjusting the concentration of glutamine in the perfusate to downregulate histone deacetylases includes decreasing the concentration of glutamine; and adjusting the concentration of butyrate in the perfusate to signal starvation includes increasing the concentration of butyrate.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 is a flow diagram of a first example of a cancer treatment method.

[0013] FIG. 2 is a flow diagram showing sub-steps of a metabolite concentration adjustment step of the cancer treatment method shown in FIG. 1.

[0014] FIG. 3 is a flow diagram of sub-steps of an alternative metabolite concentration adjustment step.

DETAILED DESCRIPTION

[0015] The disclosed cancer treatment methods will become better understood through review of the following detailed description in conjunction with the figures. The detailed description and figures provide merely examples of the various inventions described herein. Those skilled in the art will understand that the disclosed examples may be varied, modified, and altered without departing from the scope of the inventions described herein. Many variations are contemplated for different applications and design considerations; however, for the sake of brevity, each and every contemplated variation is not individually described in the following detailed description.

[0016] Throughout the following detailed description, examples of various cancer treatment methods are provided. Related features in the examples may be identical, similar, or dissimilar in different examples. For the sake of brevity, related features will not be redundantly explained in each example. Instead, the use of related feature names will cue the reader that the feature with a related feature name may be similar to the related feature in an example explained previously. Features specific to a given example will be described in that particular example. The reader should understand that a given feature need not be the same or similar to the specific portrayal of a related feature in any given figure or example.

Definitions

[0017] The following definitions apply herein, unless otherwise indicated.

[0018] “Substantially” means to be more-or-less conforming to the particular dimension, range, shape, concept, or other aspect modified by the term, such that a feature or component need not conform exactly. For example, a “substantially cylindrical” object means that the object resembles a cylinder, but may have one or more deviations from a true cylinder.

[0019] “Comprising,” “including.” and “having” (and conjugations thereof are used interchangeably to mean including but not necessarily limited to, and are open-ended terms not intended to exclude additional elements or method steps not expressly recited.

[0020] Terms such as “first”, “second”, and “third” are used to distinguish or identify various members of a group, or the like, and are not intended to denote a serial, chronological, or numerical limitation.

[0021] “Coupled” means connected, either permanently or releasably, whether directly or indirectly through intervening components.

[0022] Methods for Treating Cancer by Adjusting Selected Metabolites

[0023] With reference to the figures, methods for treating cancer by adjusting selected metabolite concentrations will now be described. The methods discussed herein function to treat cancer. In particular, the methods functions to treat cancer by utilizing specific metabolic pathways.

[0024] The reader will appreciate from the figures and description below that the presently disclosed cancer treatment methods address many of the shortcomings of conventional cancer treatment methods. For example, the novel methods below reduce or completely avoid unintended damage to tissue and organs when working to stop the growth of cancer cells. Further, the novel cancer treatment methods described herein utilize natural metabolic pathways to harness the body's inherent ability to fight cancer.

[0025] Metabolic preconditioning using the methods described below has the potential to replace neoadjuvant therapy. Metabolic preconditioning according to the methods descried herein is low cost, safe, and utilizes a clear and definitive mechanism with a high likelihood of success.

[0026] Technology has advanced enough that isolating a tumor's blood supply and supplying the tumor with a nutrient profile that promotes differentiation according to the methods discussed in this document is possible. The cancer treatment methods described herein can shrink tumors that cannot be surgically resected or are in vital organs like the brain or pancreas. Metabolic preconditioning using the methods below can dramatically reduce treatment costs and side effects. Additionally, the novel methods discussed in this document can make immunotherapy and chemotherapy more effective without off-target effects.

[0027] Cancer Treatment Method Embodiment One

[0028] With reference to FIGS. 1 and 2, a first example of a cancer treatment method, cancer treatment method 100, will now be described. As shown in FIG. 1, cancer treatment method 100 includes the steps of adjusting the concentration of selected metabolites in a blood supply to yield a perfusate at step 101 and delivering the perfusate to an artery of a patient at step 102. In some examples, the cancer treatment method does not include one or more aspects of cancer treatment method 100. In other examples, the cancer treatment method includes additional or alternative steps.

[0029] The steps of cancer treatment method 100 will be described in more detail in the sections below.

[0030] Adjusting Selected Metabolite Concentrations

[0031] As can be seen in FIG. 1, adjusting the concentration of selected metabolites in a blood supply at step 101 yields a perfusate that is delivered to a patient in step 102. The concentrations of the selected metabolites are adjusted to promote terminal cellular differentiation in a tumor. Promoting terminal cellular differentiation in the tumor functions to force the tumor to exit the cell cycle. Forcing the tumor to exit the cell cycle dramatically improves cancer cure rates, including in leukemia and endometrial cancer.

[0032] In some examples, the concentrations of selected metabolites in the blood supply are adjusted to reduce the osmotic pressure of the perfusate. Additionally or alternatively, the concentration of selected metabolites in the blood supply may be adjusted to maintain a selected redox potential of the perfusate. The selected redox potential may correspond to a selected concentration of intra-cellular glutathione that promotes apoptosis in a tumor.

[0033] In certain examples, the concentrations of selected metabolites in the blood supply are adjusted to signal starvation. Additionally or alternatively, the concentration of selected metabolites in the blood supply may be adjusted to regulate expression of the Yamanaka stem cell factors in the perfusate. Further, the concentrations of selected metabolites in the blood supply may be adjusted to restore a patient's compromised immune response to a tumor to a baseline immune response. Another basis for adjusting the concentration of selected metabolites in the blood supply is restoring extracellular oxidation reduction potential in an environment proximate a tumor to within a baseline range of an extracellular oxidation reduction potential.

[0034] With reference to FIG. 2, the reader can see the steps included in adjusting the concentration of selected metabolites in a blood supply at step 101. In the example shown in FIG. 2, adjusting the concentration of selected metabolites in a blood supply at step 101 includes adjusting the concentration of glycerol in a blood supply to yield a perfusate with reduced osmotic pressure at step 103. Step 101 further includes adjusting the concentration of ascorbic acid in the perfusate to maintain a selected redox potential at step 104. Step 101 continues with adjusting the concentration of glutamine in the perfusate to downregulate histone deacetylases at step 105. A further sub-step of step 101 is adjusting the concentration of butyrate in the perfusate to signal starvation at step 106.

[0035] The concentrations of glycerol, ascorbic acid, glutamine, and butyrate are adjusted in step 101 to selected metabolite concentrations. The metabolite concentrations resulting from the step 101 adjustments are selected to promote terminal cellular differentiation in a tumor.

[0036] Each sub-step of adjusting the concentration of selected metabolites in a blood supply at step 101 will be described in the sections below. The reader should understand, however, that some examples of adjusting the concentration of selected metabolites in a blood supply include fewer, additional, or different steps than depicted in FIG. 2. For example, FIG. 3 depicts a variation of adjusting the concentration of selected metabolites in a blood supply with different sub-steps, steps 210-213, than depicted in FIG. 2.

[0037] Adjusting the Concentration of Glycerol

[0038] Adjusting the concentration of glycerol at step 103 functions to yield a perfusate with reduced osmotic pressure. Reducing osmotic pressure controls the stem cell factor Oct4. Osmotic conditions can also be used to control endocytosis.

[0039] Cancer cells upregulate endocytosis to increase uptake of amino acids and membranes and to bias recycling of integrins and signaling receptors. Endocytosis is the rate limiting step in cadherin downregulation and is crucial for the EMT and cancer invasiveness. Endosomes integrate Tor-Akt and MAP kinase signaling, and they form the scaffold for the enzymes of nucleotide synthesis.

[0040] Hypoosmotic conditions inhibit endocytosis and promote exocytosis. Hyposmotic swelling can be achieved by exposure to membrane permeant osmolytes followed by passive transport of water. Glycerol is a nontoxic, metabolizable, membrane permeant osmolyte.

[0041] Glycerol inhibits endocytosis and induces exocytosis causing cell swelling. Unlike other membrane permeant osmolytes such as urea, glycerol induces exocytosis for long periods because it is phosphorylated and enters central metabolism.

[0042] Glycerol accumulation opposes glucose import preventing the rapid metabolism required for cell division. Respiration on glycerol and AMPK signaling physically disrupts an endosomal/mitochondrial junction necessary for rapid channeling of substrates into nucleotide synthesis. Because glycerol is a membrane permeant osmolyte it doesn't induce osmoadaptation. Thus, multiple cycles of glycerol perfusion, metabolic trapping, water influx, and cell swelling can be performed.

[0043] In the present example, step 103 includes increasing the concentration of glycerol in the perfusate. For example, the concentration of glycerol in the perfusate may be increased to 50 mM. In some example, the concentration range of glycerol in the perfusate is selected to be between 45 and 55 mM. The concentration of glycerol may be adjusted to any concentration effective to reduce osmotic pressure and control endocytosis

[0044] Adjusting the Concentration of Ascorbic Acid

[0045] Adjusting the concentration of ascorbic acid in the perfusate at step 104 functions to maintain a selected redox potential. Hyperoxia opposes transcription of stemness factors. Hyperbaric oxygen promotes better outcomes in conventional cancer treatments.

[0046] Changes in the extracellular oxidation reduction potential predict and control the immune response. The tumor microenvironment and redox state signaling predicts immune response and survival time. Hypoxia impairs beneficial macrophage polarization and determines NK cell differentiation.

[0047] Hyperbaric oxygen increases T-cell infiltration to the tumor. Regulatory T-cells use extracellular redox remodeling to suppress the immune response. Glutathione primes T-cells for inflammation. Redox signaling is key to orchestrate the immune response, and engineering these signals in the tumor environment will increase the immune response to the tumor.

[0048] The redox state can also be used to manipulate other cellular pathways. Pentose phosphate pathway (PPP) provides nucleotides for rapidly dividing cells. The PPP is regulated by dehydroascorbate. Ascorbate kills cancer stem cells, promotes expression of the cell cycle genes that inhibit cell cycle progression, and inhibits glucose consumption while stimulating lactate transport.

[0049] Using specialized perfusates to adjust the oxidation reduction potential can promote cell differentiation, impair nucleotide synthesis, and restore the cells' ability to commit apoptosis. Restoring the proper redox signaling allows the immune system to activate in the tumor microenvironment.

[0050] Intracellular redox state determines a cell's decision to self-renew, differentiate, or commit apoptosis. The intracellular reduction potential is sensed and indicated by molecules like glutathione and ascorbic acid, which are in equilibrium. Thus, adjusting the concentration of ascorbic acid enables controlling the intracellular redox potential, and, in turn, a cancer cell's tendencies to self-renew, differentiate, or commit apoptosis.

[0051] In some examples, a selected redox potential of the perfusate is maintained by adjusting the concentration of ascorbic acid (or ascorbate) in the perfusate. The selected redox potential corresponds to a selected concentration of intra-cellular glutathione that promotes apoptosis in a tumor. In some examples, the concentration of ascorbic acid is increased to between 1 and 2 mM to maintain the selected redox potential. Higher or lower ascorbic acid concentrations may be used to maintain a desired redox potential.

[0052] Adjusting the Concentration of Glutamine

[0053] Adjusting the concentration of glutamine in the perfusate at step 105 has multiple functions. One function is to downregulate histone deacetylases. A further function is to maintain expression of the stem cell transcription factor Oct4. Another function is to reduce impairments to tumor cells differentiating.

[0054] Glutamine is the major anaplerotic substrate and the initial substrate in the nucleotide synthesis that maintains cancer stem cells. Glutamine supplies aKG, which is the substrate for DNA demethylases. DNA demethylases directly impairs differentiation.

[0055] Glutamine also impairs differentiation by downregulating histone deacetylases (HDACs). Further, glutamine maintains expression of the stem cell transcription factor Oct4. Limiting the utilization of glutamine makes cells glucose dependent.

[0056] Glutamine modulates the cell redox state. Changing the redox potential promotes nucleotide synthesis. Glutamine withdrawal depletes the endogenous antioxidant glutathione (GSH) and OCT4 is subsequently inactivated via cysteine oxidation and degraded, which leads to cell differentiation.

[0057] Glutamine concentration is up to approximately 800 mM in normal conditions. In withdrawal conditions, glutamine concentration approaches approximately 200 mM. The present methods include decreasing glutamine concentrations in the perfusate to values near 200 mM. In some examples, the glutamine concentrations are decreased to between 200 mM and 260 mM. In other examples, the glutamine concentration is decreased to between 150 mM and 350 mM.

[0058] Adjusting the Concentration of Butyrate

[0059] Adjusting the concentration of butyrate in the perfusate at step 106 functions to signal starvation. Lipid metabolism heavily influences cell differentiation and expression of stem cell markers like Myc.

[0060] Myc transcription is repressed by the Myc promoter-binding protein-1 (MBP-1). MBP-1 is related to the glycolytic enzyme alpha-enolase and is regulated by hypoxia.

[0061] A ketogenic diet potentiates chemotherapies and radiation treatments and increases cancer survival. Ketone bodies like butyrate are endogenous histone deacetylase inhibitors (HDACi). Butyrate inhibits the histone deacetylases that control sternness to promote tissue differentiation.

[0062] HDACI promote differentiation, in part, by the selective depletion of Bromo Domain (BET) proteins. Depleting BET proteins directly targets transcription of Myc.

[0063] Butyrate acts in the mitochondrial apoptotic pathway. Butyrate is more effective as an HDACi if lipid metabolism is active. Supplements that accelerate lipid consumption, including alpha lipoic acid, acetylcarnitine CoQ10, or pantethine, all sensitize cancer to treatment and improve survival. Thus, as part of this metabolic therapy, to make butyrate effective as an HDAC, patients would take these supplements in conjunction with metabolite perfusion to increase the effectiveness of the butyrate therapy.

[0064] Butyrate broadly downregulates transcription, consistent with downregulation of Myc. Butyrate levels correlate with therapeutic response in anti CTLA4 and anti PD-L1 immunotherapy in melanoma. The antitumor response relies on toll-like receptor 4 (TLR)-4 signaling.

[0065] In some examples, adjusting the concentration of butyrate in the perfusate to signal starvation includes increasing the concentration of butyrate in the perfusate. In one specific example, butyrate is increased to a concentration of 6 to 8 mM in the perfusate. The concentration of butyrate may be increased to smaller or larger concentrations effective to signal starvation in cancer cells.

[0066] Delivering the Perfusate

[0067] Delivering the perfusate to an artery of a patient at step 102 functions to enable the perfusate established in step 101 to be distributed throughout the patient's body by the patient's cardiovascular system. When the perfusate is distributed throughout the patient's body, the metabolites in the perfusate at selected concentrations can interact with cells and drive beneficial terminal differentiation of tumor cells.

[0068] Delivering the perfusate at step 102 may be accomplished by any currently known or later developed means. Suitable means include hemodialysis machines, extracorporeal membrane oxygenation (ECMO) techniques and machines, and simple injections.

Additional Embodiments

[0069] With reference to the figures not yet discussed, the discussion will now focus on additional cancer treatment method embodiments. The additional embodiments include many similar or identical features to cancer treatment method 100. Thus, for the sake of brevity, each aspect of the additional embodiments below will not be redundantly explained. Rather, key distinctions between the additional embodiments and cancer treatment method 100 will be described in detail and the reader should reference the discussion above for features substantially similar between the different cancer treatment method examples.

Second Embodiment

[0070] Turning attention to FIG. 3, a second example of a cancer treatment method will now be described. The second example of a cancer treatment method includes the steps of adjusting the concentration of selected metabolites in a blood supply to yield a perfusate at step 201 and delivering the perfusate to an artery of a patient.

[0071] As can be seen in FIG. 3, adjusting the concentration of selected metabolites in a blood supply to yield a perfusate at step 201 includes different steps than corresponding step 101 in FIG. 2. With reference to FIG. 3, step 201 includes the sub-steps of reducing the concentration of glutamine in the perfusate at step 210, adjusting the concentration of ketone bodies in the perfusate at step 211, adjusting concentrations of selected metabolites to regulate expression of the Yamanaka stem cell factors at step 212, and adjusting concentrations of selected metabolites to restore a patient's baseline immune response to a tumor at step 213. The sub-steps of step 201 will be discussed in the sections below.

[0072] Adjusting the Concentration of Glutamine

[0073] Step 210 depicted in FIG. 3 involves reducing the concentration of glutamine in the perfusate to a concentration selected to reduce cysteine exporting from a tumor cell. Redox potential, cysteine, and glutamine converge upon the metabolic decisional circuitry via glutathione.

[0074] Glutathione is synthesized from glutamate and cysteine and its synthesis is dependent upon the cellular redox state. High GSH (glutathione) synthase activity maintains stem cells. Apoptosis is regulated by the intra-cellular levels of GSH and dependent upon the GSH-related redox pattern of the cell.

[0075] The importance of cysteine in stemness and failure to differentiate is evidenced by the cysteine/glutamate exchange transporter (xCT). xCT is essential for KRAS-mediated transformation. This transporter promotes stem cell properties and is implicated in very aggressive cancers, such as glioblastoma and triple negative breast cancer.

[0076] xCT activates the pentose phosphate pathway (PPP) via oxidative stress from cysteine. Import of cysteine and conversion to cysteine allows synthesis of glutathione.

[0077] Export of cysteine leads to a more reducing oxidation potential in the extracellular environment. This change in extracellular redox state helps defeat the immune response to the cancer.

[0078] Adjusting the Concentration of Ketone Bodies

[0079] Adjusting the concentration of ketone bodies in the perfusate at step 211 functions to signal starvation. As discussed above with regard to the ketone body Butyrate, ketone bodies are endogenous histone deacetylase inhibitors (HDACi). Ketone bodies inhibit the histone deacetylases that control stemness to promote tissue differentiation.

[0080] Ketone bodies broadly downregulate transcription similarly to downregulating Myc. Ketone body levels correlate with therapeutic response in anti CTLA4 and anti PD-L1 immunotherapy in melanoma. The antitumor response to ketone body levels relies on toll-like receptor 4 (TLR)-4 signaling.

[0081] In some examples, adjusting the concentration of ketone bodies in the perfusate to signal starvation includes increasing the concentration of ketone bodies in the perfusate. In one specific example, ketone bodies are increased to a concentration of 6 to 8 mM in the perfusate. The concentration of ketone bodies may be increased to smaller or larger concentrations effective to signal starvation in cancer cells.

[0082] Regulating Expression of Yamanaka Stem Cell Factors

[0083] Adjusting concentrations of selected metabolites to regulate expression of the Yamanaka stem cell factors at step 212 functions to induce pluripotency or stemness. Four Yamanaka transcription factors are sufficient to induce stemness.

[0084] Expression of the four Yamanaka transcription factors is a marker of dedifferentiation and is a negative prognostic sign in cancer. Downregulation of these markers is associated with the process of differentiation. The primordial determinants of cellular differentiation also control the stem cell factors.

[0085] OCT4 is a redox-based sensor of glutamine metabolism. Hypoosmotic signals lead to its phosphorylation and degradation. Sox2 is downregulated by hyperoxia. Hypoxia allows MYC transcription. MYC amplifies RNA expression, mitigates cellular acidity, and enhances glutamine metabolism.

[0086] Restoring a Patient's Compromised Immune Response

[0087] Restoring a patient's compromised immune response to a tumor at step 213 functions to reestablish a baseline immune response for the patient. Adjusting metabolic concentrations of selected metabolites in the perfusate enables addressing conditions where redox remodeling is disabled in a patient's immune response. Restoring redox remodeling signals enables the patient's immune response to the tumor to be restored to baseline levels rather than compromised and ineffectual levels.

[0088] Restoring a patient's compromised immune response may be accomplished by adjusting one or more concentrations of metabolites in the perfusate. The restoring concentrations may correspond to one or more of the metabolite concentration ranges above. For example, the concentration of ascorbate in the perfusate may be adjusted to 1 to 2 mM.

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[0200] The disclosure above encompasses multiple distinct inventions with independent utility. While each of these inventions has been disclosed in a particular form, the specific embodiments disclosed and illustrated above are not to be considered in a limiting sense as numerous variations are possible. The subject matter of the inventions includes all novel and non-obvious combinations and subcombinations of the various elements, features, functions and/or properties disclosed above and inherent to those skilled in the art pertaining to such inventions. Where the disclosure or subsequently filed claims recite “a” element, “a first” element, or any such equivalent term, the disclosure or claims should be understood to incorporate one or more such elements, neither requiring nor excluding two or more such elements.

[0201] Applicant(s) reserves the right to submit claims directed to combinations and subcombinations of the disclosed inventions that are believed to be novel and non-obvious. Inventions embodied in other combinations and subcombinations of features, functions, elements and/or properties may be claimed through amendment of those claims or presentation of new claims in the present application or in a related application. Such amended or new claims, whether they are directed to the same invention or a different invention and whether they are different, broader, narrower or equal in scope to the original claims, are to be considered within the subject matter of the inventions described herein.