Menthol, (+)- | C10H20O - PubChem
Test surfactants consisting of phospholipid-clove oil mixtures in the ratio of 1 part of with surfactant and oil in opposite stereochemical configurations provided ibuprofen hydrogel product (Deep Relief, Mentholatum Company Ltd., USA). Advertisement for Stop 'n Grow, Mfr: The Mentholatum Co Ltd, East. Kilbride, Scotland. .. Finar IL, Chemistry. Stereochemistry and the Chemistry of Natural Hancock Bruno Cetal “The Relationship Between the Glass Tran. Menominee's Menorah Menorca Menotti Mensa Mentholatum Mentholatum's . ODs OE OECD OED OEO OF OFris OH OHG OHSA OHSA's OJ OK OK's OKs . Roman's Romance Romance's Romanesque Romanesque's Romanesques stereo's stereobate stereochemistry stereochrome stereochromy stereogram .
As a result, proteins produced from these non-human expression systems will exhibit physiochemical and pharmacological characteristics such as half-life, antigenicity,stability and functional potency that are distinct from human cell-derived proteins. The recent advancement of stem cell technology has substantially increased the potential for utilizing stem cells in applications such as transplantation therapy, drug screening, toxicology studies and functional genomics.
However, stem cells are routinely maintained in culture medium that contains non-human proteins and are therefore not suitable for clinical applications due to the possibility of contamination with non-human infectious material. Furthermore, culturing of stem cells in non-human derived media may result in the. Nature Medicine 11 2: A summary of the sequence identifiers is provided in Table 1.
A sequence listing is provided after the claims. The present invention relates generally to an isolated protein or chimeric molecule thereof which comprises a C-type lectin or an EGF-like domain comprising a profile of physiochemical parameters, wherein the profile is indicative of, associated with, or forms the basis of one or more distinctive pharmacological traits.
As used herein the term "distinctive" with regard to a pharmacological trait of a protein or chimeric molecule thereof of the present invention refers to one or more pharmacological traits of a protein or chimeric molecule thereof which are distinctive for the particular physiochemical profile.
In a particular embodiment, one or more of the pharmacological traits of an isolated protein or chimeric molecule thereof is different from, or distinctive relative to a form of the same protein or chimeric molecule thereof produced in a prokaryotic or lower eukaryotic cell or even a higher eukaryotic cell of a non-human species.
In another embodiment, the pharmacological traits of a subject isolated protein or chimeric molecule thereof contribute to a desired functional outcome. As used herein, the term "measurable physiochemical parameters" or Px refers to one or more measurable characteristics of the isolated protein or chimeric molecule thereof.
In a particular embodiment of the present invention, the measurable physiochemical parameters of a subject isolated protein or chimeric molecule thereof contribute to or are otherwise responsible for the derived pharmacological trait, Ty.
An isolated protein or chimeric molecule of the present invention comprises physiochemical parameters Px which taken as a whole define protein molecule or chimeric molecule. A list of these parameters is summarized in Table 2.
In an embodiment, an amphiregulin of the present invention is characterized by a profile of one or more of the following physiochemical parameters Px and pharmacological traits Tycomprising: In an embodiment, a CDL-Fc of the present invention is characterized by a profile of one or more of the following physiochemical parameters Px and pharmacological traits Tycomprising: In an embodiment, a Langerin S of the present invention is characterized by a profile of one or more of the following physiochemical parameters Px and pharmacological traits Ty 5 comprising: In an embodiment, a L-selectin-Fc of the present invention is characterized by a profile of one or more of the following physiochemical parameters Px and pharmacological traits Tycomprising: These are summarized in Table 3.
The present invention further provides a chimeric molecule comprising an isolated protein or a fragment thereof, such as an extra-cellular domain of a membrane bound protein, or a a CRD or CTL domain of a type I or II membrane protein, linked to the constant Fc or framework region of a human immunoglobulin via one or more protein linker.
Such a chimeric molecule is also referred to herein as protein-Fc. Such protein-Fc has a profile of measurable physiochemical parameters indicative of or associated with one or more distinctive pharmacological traits of the isolated protein-Fc. Other chimeric molecules contemplated by the present invention include the protein or protein-Fc or a fragment thereof, linked to a lipid moiety such as a polyunsaturated fatty acid molecule.
Such lipid moieties may be linked to an amino acid residue in the backbone of the molecule or to a side chain of such an amino acid residue.
The present invention further provides a chimeric molecule comprising an isolated protein or a fragment thereof, such as an extra-cellular domain of a membrane bound protein, linked to the constant Fc or framework region of a mammalian immunoglobulin via one or more protein linker.
In another aspect, the mammal Fc or framework region of the immunoglobulin is derived from a mammal selected from the group consisting of primates, including humans, marmosets, orangutans and gorillas, livestock animals e.
In another embodiment the Fc or framework region is a human immunoglobulin. In a particular embodiment the mammal is a human. Other chimeric molecules contemplated by the present invention include the protein or protein-Fc or a fragment thereof linked to a lipid moiety such as a polyunsaturated fatty acid molecule. Such lipid moieties may be linked to an amino acid residue in the background of the molecule or to a side chain of such an amino acid residue.
The chimeric molecules of the present invention, including amphiregulin-Fc, CDL-Fc, Langerin-Fc, L-selectin-Fc have a profile of measurable physiochemical parameters indicative of or associated with one or more distinctive pharmacological traits of the isolated protein-Fc. In addition, the present invention provides a novel chimeric Langerin molecule comprising a complete or a fragment of Langerin molecule comprising one or more of heptad repeat, alpha helical coiled coil neck region stalkC-type carbohydrate-recognition domain CRD or C-type lectin CTL or CTL-like domains linked to the complete or a fragment of a signal peptide of ILlOR alpha directly or via one or more protein linkers.
Such a chimeric Langerin molecule may have a profile of measurable physiochemical parameters indicative of or associated with one or more distinctive pharmacological traits of the isolated chimeric Langerin molecule.
In one embodiment, the chimeric Langerin molecule comprises the CRD region of an isolated Langerin molecule linked to the complete or a fragment of a signal peptide of ILlOR alpha directly or via one or more protein linkers.
Such a chimeric molecule is also referred to herein as Langerin short, Langerin S. In another embodiment, the chimeric Langerin molecule comprises the CRD region and the stalk region of an isolated Langerin molecule linked to a complete or a fragment of a signal pepetide of ILlOR alpha directly or via one or more protein linkers.
Such a chimeric molecule is also referred to herein as Langerin long, Langerin L. Accordingly, the present invention provides an isolated polypeptide encoded by a nucleotide sequence selected from the list consisting of SEQ ID NOs: Yet another aspect of the present invention provides an isolated polypeptide comprising an amino acid sequence selected from the list consisting of SEQ ID NOs: With respect to the primary structure, the present invention provides an isolated protein or chimeric molecule thereof, or a fragment thereof, encoded by a nucleotide sequence selected from the list consisting of SEQ ID NOs: In another aspect, the present invention provides an isolated nucleic acid molecule encoding a protein or chimeric molecule which comprises a C-type lectin or an EGF-like domain, selected from the group comprising amphiregulin, CDL, Langerin, L-selectin, or a fragment thereof, comprising a sequence of nucleotides selected from the group consisting of SEQ ID NOs: In another aspect, the present invention provides an isolated protein in or related to the which comprises a C-type lectin or an EGF-like domain, selected from the group comprising amphiregulin, CDL, Langerin, L-selectin, or a fragment thereof, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: More particularly, the present invention extends to a method of treating or preventing a condition or ameliorating the symptoms of a condition in an animal subject, said method comprising administering to said animal subject an effective amount of an isolated protein or chimeric molecule thereof.
The present invention further contemplates using an isolated protein or chimeric molecule thereof as immunogens to generate antibodies for therapeutic or diagnostic applications.
Active agents include A - D: B camphor oil, including camphor white oil from which camphor has been substantially removed by distillation, and constituents of camphor oil. Camphor oil is a complex mixture that includes various constituents. Two different lots of camphor white oil, were tested and the constituents are set forth in Table 2.
All of these are active agents for the purpose of embodiments of the invention. C Camphor white oil was used for most of the in vivo tumor experiments; the in vitro experiments with tumor cells were done with camphor and 2-APB. Camphor white oil constituents include: As such it is used in sunscreen lotions and other skincare products claiming a SPF value. Norcamphor is a chemical compound, classified as a ketone, which is an analog of camphor without the three methyl groups.
The administering can also be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchymally or microinjection.
Agonists may or may not be homologous to these natural compounds in respect to conformation, charge or other characteristics. The preferred animal, patient, or subject is a human. An individual having one or more of these risk factors has a higher probability of developing SCC than an individual without these risk factors. It is an organic compound of the isoprenoid family that belongs to the group of bicyclic monoterpenes.
A white, waxy solid with a penetrating, somewhat musty aroma, it is obtained from the wood of the camphor laurel laurel familyCinnamomum camphora found in Asiaor produced synthetically from oil of turpentine. It exists in the optically active dextro and levo forms, and as the racemic mixture of the two forms.
The principal form is dextro-camphor, which occurs in the wood and leaves of the camphor tree Cinnamomum camphora. Camphor is also synthesized commercially on a large scale from pinene, which yields mainly the racemic variety.
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Camphor is readily absorbed through the skin and produces substance feeling of warmth, and acts as a slight local anesthetic and anti-itch substance. There are anti-itch gels and soothing gels with camphor as the active ingredient.
Camphor is an active ingredient along with menthol in vapor-steam products, such as Vicks VapoRub. It is extracted from the wood by steam distillation. Camphor oil may be a natural extract or a synthetic mixture of components e. A natural extract or naturally derived camphor oil may have a different composition from lot to lot from that of a synthetic camphor oil. Terpenes other than camphor are major constituents of camphor oil.
Several of these, including linalool, alpha-pinene, limonene dipenteneand geraniol are TRPV3 agonists. Cancer includes high-risk forms of SCC and high-risk non-melanoma skin cancers and neoplastic conditions, whether characterized as malignant, benign, soft tissue, or solid, and cancers of all stages and grades including pre- and post-metastatic cancers. SCC cancers that can appear on the skin, lips, mouth, lung, head, stomach, prostate, colon, rectum, throat, urinary tract, reproductive tract, and esophagus.
Precancerous lesions are also referred to in the literature often as a papillomas. This may include, but is not limited to a variation in stereochemistry to either increase or decrease the size of a ring, or such as an addition or deletion of a substituent, or a variation in functional group, or an analog.
Certain camphor oil and 2-APB derivatives or analogs are known in the art e. Surgery alone is not enough to treat these high-risk SCCs, so adjuvant radiotherapy and chemotherapy are given with continued monitoring due to the metastatic nature of the disease. In the general literature prior to the discoveries described herein, a diagnosis of high-risk SCC was based entirely on a battery of clinical and histological criteria because there was no known biological marker.
In general a surgeon refers to a high-risk SCC as one that that has a greater risk for recurrence following treatment and metastasis, based on the following criteria: History of irradiation to skin; 7. History of recurrence following previous treatment. Poorly differentiated histology 3.
Perineural invasion The high-risk form of SCC and the high-risk forms of other non-melanoma cancers herein described have now been discovered to be dysregulated for TRP ion channel expression so that they can be diagnosed if they expresses either significantly higher or significantly lower than normal levels of one or more of the proteins of TRPV3, TRPV1, TRPA1, and TRPC1 that are now discovered to be biomarkers of high-risk SCC and non-melanoma cancers.
In certain embodiments, the manufacture may be promoted, distributed, or sold as a unit for performing the methods of the present invention. Most of them are fragrant and form major constituents of many plant-derived essential oils.
The full prophylactic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. Samples include, without limitation, a tissue sample e. A biopsy of cells of a solid tumor or of skin suspected of having SCC including high-risk formsnon-melanoma cancers including high-risk formsor AK, can be obtained using any technique known in the art.
Means from qPCR technical replicates typically per sample were compared with Student's t tests two-tailed. SCC is one of the major forms of skin cancer.
However, squamous cells also occur in the lining of the digestive tract, lungs, and other areas of the body, and SCC occurs as a form of cancer in diverse tissues, including the lips, mouth, esophagus, urinary bladder, prostate, lung, vagina, and cervix, among others. SCC is a histologically distinct form of cancer arising from the uncontrolled multiplication of cells of epithelium, or cells showing particular cytological or tissue architectural characteristics of squamous cell differentiation, such as the presence of keratin, tonofilament bundles, or desmosomes, structures involved in cell-to-cell adhesion.
Squamous cell carcinomas are at least twice as frequent in men as in women. They rarely appear before age fifty and are most often seen in individuals in their seventies. The majority of skin cancers in African-Americans are squamous cell carcinomas, usually arising on the sites of preexisting inflammatory skin conditions or burn injuries. Some terpenes are major constituents of camphor oil. Several of these, including linalool, pinene, limonene dipentenegeraniol and borneol are TRPV3 agonists.
The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations per day for successive days. There are about 28 TRP channels that share some structural similarity to each other.
These are grouped into two broad groups: Many of these channels mediate a variety of sensations like the sensations of pain, hotness, warmth or coldness, different kinds of tastes, pressure, and vision.
In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic allicinchilli pepper capsaicinwasabi allyl isothiocyanate ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis i.
CROSS-REFERENCE TO RELATED APPLICATIONS
Some act as sensors of osmotic pressure, volume, stretch, and vibration. The TRPV3 channel is widely expressed in the human body, especially in the skin in keratinocytes, but also in the brain.
It is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. For purposes of this invention, beneficial or desired clinical results include, but are not limited to alleviation or amelioration of one or more symptoms of the SCC cancer including high-risk formsor non-melanoma cancers including high-risk formsor AK; diminishing the extent of disease; delaying or slowing disease progression; amelioration and palliation or stabilization of the disease state.
For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized i. Those in need of treatment include those already having cancer and those with benign tumors or precancerous lesions. Experiments showed that human biopsy-derived SCC cells cultured in vitro in a preclinical organotypic model responded to the topical application of the terpene TRPV3 agonist, 2-APB or camphor, by showing reduced cancer cell proliferation which in turn reduced tumor burden and invasiveness.
Topical application of camphor white oil in vivo promoted regression of pre-malignant SCC skin tumors, slowed progression of benign tumors to SCC; suppressed SCC invasion; and dramatically attenuated malignant SCC conversion in vivo.
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Topical camphor-oil treatment was also sufficient to clear apparent tumors in a subset of animals in carcinogenesis models in vivo. Alternatively, these terpenes might modulate the tumor microenvironment in ways that attenuate tumor cell growth e.
It has also been discovered that high-risk SCC or high-risk non-melanoma skin cancer can be diagnosed by determining in a biopsy of a keratinocyte lesion from a subject if the level of expression of one or more TRP channels, including TRPV3, TRPC1, TRPV1, TRPA1, is either significantly higher or significantly lower compared to the corresponding level in normal skin, either from the same or a different subject.
Overview The incidence of human squamous cell carcinomas and non-melanoma skin cancer is at an all-time high Ratushny et al.
Although the standard of care e. For example, SCCs that develop in chronic immunosuppression, such as in organ transplant recipients and patients with HIV, are frequently highly aggressive and potentially fatal tumors. Little is known about the pathophysiological mechanisms underlying keratinocyte-derived skin cancers and their relation to normal keratinocyte growth and differentiation. A better understanding of normal keratinocyte maturation is critical for unmasking the pathophysiological changes resulting in tumorigenesis.
Environmental factors and genetic alterations that contribute to keratinocyte-derived skin cancers have been identified; however, a better understanding of normal keratinocyte physiology is critical for unmasking pathophysiological changes resulting in tumorigenesis. Non-melanoma skin cancers are the most common cancers in the United States.
As non-melanoma skin cancers typically exhibit perturbed patterns or dramatic loss of keratinocyte differentiation, it is important to determine the role for the calcium ion channels TRPV3, TRPV1, TRPA1, and TRPC1 in human keratinocyte maturation and its potential as a target for skin cancer therapy.
Squamous Cell Carcinoma SCC is a cancer of a kind of epithelial cell, the squamous cell that makes up the main part of the epidermis of the skin. However, squamous cells also occur in the lining of the digestive tract, lungs, and other areas of the body, and SCC occurs as a form of cancer in diverse tissues, including the lips, oral mucosa, nasopharynx, esophagus, urinary bladder, prostate, lung, vagina, and cervix, among others.
They rarely appear before age 50 and are most often seen in individuals in their 70s. Squamous cell carcinoma is the second-most common cancer of the skin after basal cell carcinoma and it is more common than melanoma.
World-wide, it is the most common cancer that has the potential to metastasize. It usually occurs in areas exposed to the sun. Sunlight exposure and immunosuppression are risk factors for SCC of the skin, with chronic sun exposure being the strongest environmental risk factor. Other risk factors include fair skin, age, male gender, history of skin cancer, and smoking. There is a risk of metastasis, often spreading to the lymph nodes, starting more than 10 years after diagnosable appearance of SCC.
The risk of SCC metastasis is low, though it is much higher than with basal cell carcinoma. SCC of the skin in individuals on immunotherapy or suffering from lymphoproliferative disorders i. Squamous cell carcinoma is generally treated by surgical excision or Mohs surgery after biopsy. Other high-risk factors for SCC include the immune status of the subject immune compromised subjects have a higher risk of SCCand whether or not the abnormal cells involve the nervous system.
High-risk forms of SCC and non-melanoma cancers are aggressive and therefore require more aggressive surgery including taking wider margins, cutting deeper, and removing lymph nodes as well as adjuvant therapy, than is needed if the SCC is not high-risk. Until now, there were no biomarkers for distinguishing high-risk from non-high-risk SCC and non-melanoma cancer. It has now been discovered that either a significantly higher or significantly lower level of mRNA encoding one or more of the following: Therefore, SCC and non-melanoma biopsies, especially OTR or other immunocompromised patients, can now be tested to determine whether they are high-risk by determining if the expression of one or more of these biomarkers is significantly higher or significantly lower compared to a corresponding level in a normal subject.
If the SCC or the non-melanoma is a high-risk cancer, it warrants aggressive treatment: If the over or underexpression of the one or more of the biomarkers is detected in a biopsy from a subject, it is recommended that treatment, be started as soon as possible, even before the biopsy results are received. Non-surgical options for the treatment of cutaneous SCC include topical chemotherapy, topical immune response modifiers, photodynamic therapy PDTradiotherapy, and systemic chemotherapy.
Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous SCC. At this time, systemic chemotherapy is used exclusively for patients with metastatic disease. Mohs surgery, also known as chemosurgery, enables the surgeon to obtain complete margin control during removal of a skin and it allows for the removal of a skin cancer with very narrow surgical margin and a high cure rate.
AKs are pre-cancerous lesions, as some progress to squamous cell carcinoma, so treatment is recommended. People who take immunosuppressive drugs, such as organ transplant patients, are times more likely to develop AK that may lead to skin cancer. Medicated creams and solutions are typically used topically to treat actinic keratosis. The use of topical therapy, such as Imiquimod cream and PDT is generally limited to premalignant i.
Rubbed gently onto the lesions once or twice a day for two to four weeks, it produces cure rates of up to 93 percent. It is rubbed gently on the lesion twice a week for four to sixteen weeks. Diclofenac is a non-steroidal anti-inflammatory drug used in combination with hyaluronic acid. The resulting gel is applied twice a day for two to three months to prevent an inflammatory response, so this topical is well-tolerated.
The hyaluronic acid delays uptake of the diclofenac, leading to higher concentrations in the skin. The gel, used in 0. Certain embodiments are directed to pharmaceutical formulations for topical applications of the above listed formulations that further include one or more of the active agents as described herein. Cryosurgery is the most commonly used treatment method when a limited number of lesions exist. Other treatment includes laser surgery, and photodynamic therapy. Keratinocytes express TRPV3 and TRPV4, and mutations in these receptors cause epidermal abnormalities such as barrier defects and hyperkeratosis Cheng et al, ; Chung et al, b; Kida et al, ; Lin et al, TRPV3 receptors are mechanistically distinct from voltage-gated calcium channels.
Voltage-gated calcium channels respond to membrane depolarization and open to permit an influx of calcium from the extracellular medium that result in an increase in intracellular calcium levels or concentrations. TRPV3 proteins are thermo sensitive channels expressed in skin cells. Initial experiments began with camphor and 2-APB, then moved to camphor white oil and various constituents and derivatives thereof.