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Cancer remains a significant global challenge, with escalating incidence rates and a substantial burden on healthcare systems worldwide. Herein, we present an in-depth exploration of the intricate interplay between cancer cell death pathways and tumor immunity within the tumor microenvironment (TME). We begin by elucidating the epidemiological landscape of cancer, highlighting its pervasive impact on premature mortality and the pronounced burden in regions such as Asia and Africa. Our analysis centers on the pivotal concept of immunogenic cell death (ICD), whereby cancer cells succumbing to specific stimuli undergo a transformation that elicits robust anti-tumor immune responses. We scrutinize the mechanisms underpinning ICD induction, emphasizing the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) as key triggers for dendritic cell (DC) activation and subsequent T cell priming. Moreover, we explore the contributions of non-apoptotic RCD pathways, including necroptosis, ferroptosis, and pyroptosis, to tumor immunity within the TME. Emerging evidence suggests that these alternative cell death modalities possess immunogenic properties and can synergize with conventional treatments to bolster anti-tumor immune responses. Furthermore, we discuss the therapeutic implications of targeting the TME for cancer treatment, highlighting strategies to harness immunogenic cell death and manipulate non-apoptotic cell death pathways for therapeutic benefit. By elucidating the intricate crosstalk between cancer cell death and immune modulation within the TME, this review aims to pave the way for the development of novel cancer therapies that exploit the interplay between cell death mechanisms and tumor immunity and overcome Challenges in the Development and implementation of Novel Therapies. [ABSTRACT FROM AUTHOR]

Background: The frass of several herbivorous insect species has been utilised as natural medicines in Asia; however, the metabolite makeup and pharmaceutical activities of insect frass have yet to be investigated. Oligophagous Papilionidae insects utilise specific kinds of plants, and it has been suggested that the biochemicals from the plants may be metabolised by cytochrome P450 (CYP) in Papilionidae insects. In this study, we extracted the components of the frass of Papilio machaon larvae reared on Angelica keiskei, Oenanthe javanica or Foeniculum vulgare and examined the biological activity of each component. Then, we explored the expression of CYP genes in the midgut of P. machaon larvae and predicted the characteristics of their metabolic system. Results: The components that were extracted using hexane, chloroform or methanol were biochemically different between larval frass and the host plants on which the larvae had fed. Furthermore, a fraction obtained from the chloroform extract from frass of A. keiskei-fed larvae specifically inhibited the cell proliferation of the human colon cancer cell line HCT116, whereas fractions obtained from the chloroform extracts of O. javanica- or F. vulgare-fed larval frass did not affect HCT116 cell viability. The metabolites from the chloroform extract from frass of A. keiskei-fed larvae prevented cell proliferation and induced apoptosis in HCT116 cells. Next, we explored the metabolic enzyme candidates in A. keiskei-fed larvae by RNA-seq analysis. We found that the A. keiskei-fed larval midgut might have different characteristics from the O. javanica- or F. vulgare-fed larval metabolic systems, and we found that the CYP6B2 transcript was highly expressed in the A. keiskei-fed larval midgut. Conclusions: These findings indicate that P. machaon metabolites might be useful as pharmaceutical agents against human colon cancer subtypes. Importantly, our findings show that it might be possible to use insect metabolic enzymes for the chemical structural conversion of plant-derived compounds with complex structures. [ABSTRACT FROM AUTHOR]

Polyalthia longifolia var. angustifolia Thw. (Annonaceae), is a famous traditional medicinal plant in Asia. Ample data specifies that the medicinal plant P. longifolia has anticancer activity; however, the detailed mechanisms of action still need to be well studied. Recent studies have revealed the cytotoxicity potential of P. longifolia leaf against HeLa cells. Therefore, the current study was conducted to examine the regulation of miRNAs in HeLa cancer cells treated with the standardized P. longifolia methanolic leaf extract (PLME). The regulation of miRNAs in HeLa cancer cells treated with the standardized PLME extract was studied through Illumina, Hi-Seq. 2000 platform of Next-Generation Sequencing (NGS) and various in silico bioinformatics tools. The PLME treatment regulated a subset of miRNAs in HeLa cells. Interestingly, the PLME treatment against HeLa cancer cells identified 10 upregulated and 43 downregulated (p < 0.05) miRNAs associated with apoptosis induction. Gene ontology (GO) term analysis indicated that PLME induces cell death in HeLa cells by inducing the pro-apoptotic genes. Moreover, the downregulated oncomiRs modulated by PLME treatment in HeLa cells were identified, targeting apoptosis-related genes through gene ontology and pathway analysis. The LC--ESI--MS/MS analysis identified the presence of Vidarabine and Anandamide compounds that were previously reported to exhibit anticancer activity. The findings of this study obviously linked the cell cytotoxicity effect of PLME treatment against the HeLa cells with regulating various miRNAs expression related to apoptosis induction in the HeLa cells. PLME treatment induced apoptotic HeLa cell death mechanism by regulating multiple miRNAs. The identified miRNAs regulated by PLME may provide further insight into the mechanisms that play a critical role in cervical cancer, as well as novel ideas regarding gene therapeutic strategies. [ABSTRACT FROM AUTHOR]

Eurycoma longifolia Jack is one of traditional herbal medicines in South-East Asia. This study evaluated the anticancer, cell-cycle arrest, and apoptotic induction potentials of eurycomanone (EONE) and eurycomanol (EOL), highly oxygenated quassinoids previously isolated from its roots, against large (H460) and small (A549) lung cancer cells. EOL and EONE exhibited IC50 of 386 and 424 µg/mL on normal human lung cell line. EONE exhibited higher anticancer activity with an IC50 of 1.78 µg/mL and 20.66 μg/mL than EOL which exhibited an IC50 of 3.22 µg/mL and 38.05 µg/mL against H460 and A549, respectively. Both reduced the viability of H460 and A549 and arrested G0/G1 phase. The increase in the apoptotic rates was mainly in the percentage of late apoptosis. Moreover, they inhibited A549 by inducing the accumulation of S and G2/M phases. This study revealed EOL and EONE potential as novel leads exhibiting cell-cycle arrest and apoptosis induction potentials. [ABSTRACT FROM AUTHOR]

Clitoria ternatea is a native plant with medicinal and nutritive significance in Asia. The goal of this work was to examine the antiproliferative role of Clitoria ternatea against colorectal (HCT116), breast (MCF-7), and thyroid (TT) cancer cell lines at cellular and molecular levels. A phytochemical analysis, the cytotoxic effect, an apoptotic induction cell cycle analysis, and the expression level of GAX, DIABLO, and NAIP1 genes were assessed. The plant extract exhibited a clear cytotoxic action against the utilized cancer cell lines via a low IC50, foremost by means of cell cycle arrest at the pre-G0, G1, and S phases associated with an apoptotic induction. An apparent raise in the mRNA levels of GAX and DIABLO and a concomitant decrease in the NAIP1 mRNA level were observed in the used cancer cells treated with the IC50 of the plant extract. This study concluded that an ethanolic extract of Clitoria ternatea induced apoptotic cell death, suggesting that it could possibly be utilized as a new source of an apoptosis-inducing anticancer agent for colon, breast, and medullary thyroid cancer cell line treatments with further detailed studies. [ABSTRACT FROM AUTHOR]

• The A549 cells treated with Cassia auriculata ethanolic extract (CAEE) revealed low cell survival rate on MTT assay compared to L132 cells. • Treated cells exhibited nuclear morphological changes indicating the apoptotic mode of cell death upon various fluorescent staining techniques like DAPI, AO/EB & PI. • An augment in the levels of procaspase 9 by CAEE indicated the ability of drug to induce apoptosis in A549 lung cancer cells. • Up-regulation in the expression of the caspase 9 gene was observed after treatment with CAEE with a fold change of 3.81- at 50 µg/ml dose. Cassia auriculata is an ethnobotanically important traditional medicinal plant of tropical Asia and recently, phytochemicals and their derivatives have gained scientific attention for their use as agents in cancer treatment and prevention. The aerial parts of Cassia auriculata plant were subjected to successive cold maceration to yield four fractions viz., n-hexane, dichloromethane, ethyl acetate, and ethanol extract. The extracts were fractionated by GC–MS (Gas Chromatography-Mass Spectrometry) and HPLC (High-Performance Liquid Chromatography) analysis for their phytochemical content. The chromatographic techniques revealed the presence of mainly the flavonoid compounds like flavone, chrysin, and quercetin. The anti-proliferative properties of ethanolic extract of C. auriculata on A549 human lung cancer cells have been reported. The cancer cell survival rate (MTT 3- [4, 5- dimethythiazol-2-yl] 2, 5-diphenyl tetrazolium bromide) was found to be reduced with lung cancer cells (IC 50 26.24 μg/ml) when treated with C. auriculata ethanol extract (CAEE) when compared to the non-cancerous cells L132. The toxicity of the extract on L132 cells was low (IC 50 55.78 μg/ml). The mode of cell death induced by CAEE on A549 cells was examined by various fluorescent staining techniques and characteristic nuclear and morphological changes for apoptosis were evaluated. The expression of caspase 9 activity was documented, which might have triggered cell death through apoptosis by the activation of caspase 9 in the ethanolic fraction treated A549 cells. Cell cycle analysis of treated A549 cells revealed a promising S phase cell cycle arrest. The flavonoid compounds identified in the present study might be responsible for the remarkable anticancer and other activities of the plant. From these findings, the plant C. auriculata can be further exploited to develop promising candidate molecules, particularly for lung cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Considering the high metastatic potential of colorectal cancer (CRC), the inhibition of metastasis is important for anti-CRC therapy. Agrimonia pilosa Ledeb (A. pilosa) is a perennial herbaceous plant that is widely distributed in Asia. The extracts of A. pilosa have shown diverse pharmacological properties, such as antimicrobial, anti-inflammatory, and antitumor activities. In the present study, the antimetastatic activity of A. pilosa was evaluated. Methanol extraction from the roots of A. pilosa was performed by high-performance liquid chromatography (HPLC) and 12 fractions were obtained. Among these, fraction 4 showed the most potent inhibitory effect on the migration of colon cancer cells. Using LC-HR MS analysis, quercetin and quercitrin were identified as flavonoids contained in fraction 4. Like fraction 4, quercetin and quercitrin effectively inhibited the migration and invasion of RKO cells. While the level of E-cadherin was increased, the levels of N-cadherin and vimentin were decreased by the same agents. Although they all activate the p38, JNK, and ERK signaling pathways, only SP600125, an inhibitor of the JNK pathway, specifically inhibited the effect of fraction 4, quercetin, and quercitrin on cell migration. An in vivo experiment also confirmed the antitumor activity of quercetin and quercitrin. Collectively, these results suggest that A. pilosa and its two flavonoids, quercetin and quercitrin, are candidates for the antimetastatic treatment of CRC. [ABSTRACT FROM AUTHOR]

6,8‐Diprenylorobol is a natural compound mainly found in Glycyrrhiza uralensis fisch and Maclura tricuspidata, which has been used traditionally as food and medicine in Asia. So far, the antiproliferative effect of 6,8‐diprenylorobol has not been studied yet in colon cancer. In this study, we aimed to evaluate the antiproliferative effects of 6,8‐diprenylorobol in LoVo and HCT15, two kinds of human colon cancer cells. 6,8‐Diprenylorobol inhibited the proliferation of LoVo and HCT15 cells in a dose‐ and time‐dependent manner. A 40 μM of 6,8‐diprenylorobol for 72 h reduced both of cell viability under 50%. After treatment of 6,8‐diprenylorobol (40 and 60 μM) for 72 h, late apoptotic cell portion in LoVo and HCT15 cells were 24, 70% and 13, 90%, respectively, which was confirmed by checking DNA fragmentation in both cells. Mechanistically, 6,8‐diprenylorobol activated p53 and its phosphorylated form (Ser15, Ser20, and Ser46) expression but suppressed Akt and mitogen‐activated protein kinases (MAPKs) phosphorylation in LoVo and HCT15 cells. Interestingly, 6,8‐diprenylorobol induced the generation of intracellular reactive oxygen species (ROS), which was attenuated with N‐acetyl cysteine (NAC) treatment. Compared to the control, 60 μM of 6,8‐diprenylorobol caused to increase ROS level to 210% in LoVo and HCT15, which was reduced into 161% and 124%, respectively with NAC. Furthermore, cell viability and apoptotic cell portion by 6,8‐diprenylorobol was recovered by incubation with NAC. Taken together, these results indicate that 6,8‐diprenylorobol has the potential antiproliferative effect against LoVo and HCT15 colon cancer cells through activation of p53 and generation of ROS. [ABSTRACT FROM AUTHOR]

Sanghuangporus is a traditional medicine that has been used for nearly 2000 years in Asia. It has been found to enhance immunity and have anticancer properties. Some studies determined that Sanghuangporus polysaccharide can inhibit tumors in vitro, although the underlying mechanisms remain unknown. Therefore, the present study investigated the antitumor effects of polysaccharides from the fruiting body of S. vaninii and their associated mechanisms. Water-soluble S. vaninii polysaccharide (SVP) with a molecular weight of 3.156 × 104 Da was isolated and found to be mainly composed of mannose, rhamnose, glucuronic acid, galacturonic acid, glucosamine, glucose, galactosamine, galactose, xylose, arabinose, and fucose in molar ratios of 1.63:0.04:0.36:0.03:0.13:8.39:0.08:1.08:0.25:1.07:0.40. SVP showed modest anti-proliferative activity against HeLa, SHG-44, SMMC-7721, and MCF-7 cells. Furthermore, it effectively regulated cell cycle, promoted apoptosis, and reduced the migratory and invasive capacities of MCF-7 cells. Mechanistically, SVP enhanced activation of p53-related genes and down-regulated MMP expression. These findings describe a potential natural polysaccharide for tumor therapy and a basis for the development of fungal polysaccharides as a type of health food. [ABSTRACT FROM AUTHOR]

The fruit of Arctium lappa L. (Arctii Fructus) is one of the most popularly used medicinal plant components in Asia. To enhance the functionality of Arctii Fructus extract, a bioconversion method was developed to produce arctigenin from arctiin. Treatment with β‐glucosidase increased the arctigenin content by >5 fold in Arctii Fructus extracts. The bioconversion products enhanced the apoptosis of cancer cells. The cell viabilities of gefitinib‐resistant lung cancer HCC827 (HCC827GR) cells and colon cancer cells (DLD1) were decreased by 40% and 35%, respectively. The bioconversion products also decreased anchorage‐independent growth of cancer cells. In addition, the increase of apoptosis in cancer cells by bioconversion was confirmed by the flow cytometry analysis. These results indicated that arctigenin exerts anticancer effects on lung and colon cancer cells and that Arctii Fructus can potentially function as a chemopreventive agent. In addition, bioconverted Arctii Fructus extract displayed higher anticancer activity than the same levels of purified arctigenin, indicating the advantage of consuming Arctii Fructus itself as a food or medicinal material. [ABSTRACT FROM AUTHOR]

Andrographolide is a labdane diterpenoid from Andrographis paniculata and has been used in the clinic for several decades to treat a variety of diseases in east Asia. In the present study, modification of 12-thioether andrographolide was carried out to seek compounds with better antitumor activity and drug-like properties. A series of novel 3,19-modified thioether andrographolide derivatives were synthesized and evaluated for their in vitro anticancer activities against human breast cancer cells. The results are promising and important in the further development of anticancer agents. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer worldwide and in Indonesia. Kaempferia pandurata Roxb. is a herbal plant from South-East Asia which is known for its ability to inhibit the growth of Estrogen Receptor (ER) + breast cancer cell line from the former study. However, its effect on ER- breast cancer cell lines had not been studied. Therefore, we want to examine the cytotoxicity effect of K. pandurata Roxb. on ER- breast cancer cell line (MDA-MB-231). Nanoparticle is a form of preparation that optimizes the activity of any compound to the targeted cell. Therefore, it is expected that it can increase the effectivity of anticancer in Kaempferia pandurata Roxb. In this study, the rhizome of K. pandurata Roxb. trituration was dried and extracted with n-hexane solvent. Nanoparticle of K. pandurata Roxb. was synthesized with CaCl2, chitosan, and alginate by stirring with a magnetic stirrer, adjusting pH, and centrifugation. Then, nanoparticle was analized by UV/VIS spectrofotometry and transmission electron microscopy (TEM). The cytotoxicity of K. pandurata Roxb. extract and nanoparticle were examined with MTT assay. The result of this test is data of inhibition percentage and IC50 value. The result showed that n-hexane extract of K. pandurata Roxb. is synthesized into nanoparticle form with 99,43% yield percentage (entrapment value). Anticancer activity of n-hexane extract and nanoparticle of K. pandurata Roxb. is moderate with IC50 value of the extract is 87,23 μg/ml and the nanoparticle is 24,23 μg/ml. The nanoparticle's activity is better than the extract. n-Hexane extract and nanoparticle of K. pandurata Roxb. has cytotoxicity effects towards MDA-MB-231 cell line. Nanoparticle can increase the cytotoxicity effect of K. pandurata Roxb. extract because its hydrophobic feature and nanometer size. [ABSTRACT FROM AUTHOR]

Background: Genus Kalanchoe (Crassulaceae) comprises plants originating from Africa and Asia. Their pharmaceutical preparations are commercially available in the form of anti-inflammatory and antimicrobial medicaments. Recent studies have shown anticancer activity of Kalanchoe plants. However, studies on Kalanchoe blossfeldiana (KB) are extremely limited, and its cytotoxic properties have not yet been evaluated. Objective: The objective of the study is to estimate the cytotoxic activity of KB on human cervical carcinoma (HeLa) cells and determine the mode of cell death. Materials and Methods: The cytotoxic activity of ethanolic extract of leaves of KB was tested on HeLa cells using Real Time xCelligence System (RTCA) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell death, the generation of reactive oxygen species (ROS), depolarization of the mitochondria, cell cycle arrest, and the activity of caspases-3/7/9 were assessed by flow cytometry or a luminometer. The activity of poly (ADP-ribose) polymerase (PARP), translocation of apoptosis-inducing factor (AIF) in the cells, and expression of 92 genes associated with apoptosis/necrosis were also estimated. Results: According to the results, the IC50values of KB extract were 8.28 ± 0.29 and 9.63 ± 1.07 μg/mL in RTCA and MTT assay, respectively. The results showed a significant increase in the generation of ROS and depolarization of the mitochondria in the dead cell population. Caspases-3/7/9 were not activated during treatment with KB extract. We also found that the pathway of HeLa cell death was induced by tumor necrosis factor-related apoptosis-inducing ligand and was independent of the PARP and AIF. The extract also induced cell cycle arrest in S phase. Conclusions: The results of this study indicate that KB extract induces necrosis in HeLa cells and this process is death receptor-mediated leading to the overproduction of ROS, mitochondrial dysfunction, and cell cycle arrest. [ABSTRACT FROM AUTHOR]

The stem bark of Ailanthus altissima is used in traditional medicine in Asia to treat a variety of diseases, including cancer. The aim of this study was to identify compounds with tumoricidal activity from A. altissima stem bark and to investigate their mechanisms of action. Among the 13 compounds isolated from the ethyl acetate fraction of A. altissima stem bark, the β-carboline alkaloid 9-hydroxycanthin-6-one had potent cytotoxicity in all three ovarian cancer cell types examined. 9-Hydroxycanthin-6-one induced apoptosis through the activation of caspases-3, -8, and -9. 9-Hydroxycanthin-6-one increased the intracellular levels of reactive oxygen species (ROS), and pre-treatment with the antioxidant N-acetyl- l -cysteine (NAC) attenuated the pro-apoptotic activity of 9-hydroxycanthin-6-one. Additionally, 9-hydroxycanthin-6-one was found to decrease the expressions of MCP-1 and RANTES, major determinants of macrophage recruitment at tumor sites, in ovarian cancer cells. Treatment with 9-hydroxycanthin-6-one inhibited the levels of M2 phenotype markers and some cancer-promoting factors, such as MMP-2, MMP-9, and VEGF, in macrophages educated in ovarian cancer conditioned medium. Taken together, these data suggest that 9-hydroxycanthin-6-one isolated from A. altissima stem bark induces apoptosis in human ovarian cancer cells through the caspase- and ROS-dependent pathways and inhibits the activation of tumor-associated macrophages. [ABSTRACT FROM AUTHOR]

Background: Birt-Hogg-Dubé (BHD) syndrome is a rare inherited autosomal genodermatosis and caused by germline mutation of the folliculin (FLCN) gene, a tumor suppressor gene of which protein product is involved in mechanistic target of rapamycin (mTOR) signaling pathway regulating cell growth and metabolism. Clinical manifestations in BHD syndrome is characterized by fibrofolliculomas of the skin, pulmonary cysts with or without spontaneous pneumothorax, and renal neoplasms. There has been no pulmonary neoplasm reported in BHD syndrome, although the condition is due to deleterious sequence variants in a tumor suppressor gene. Here we report, for the first time to our knowledge, a patient with BHD syndrome who was complicated with a clear cell "sugar" tumor (CCST) of the lung, a benign tumor belonging to perivascular epithelioid cell tumors (PEComas) with frequent causative relation to tuberous sclerosis complex 1 (TSC1) or 2 (TSC2) gene. Case presentation: In a 38-year-old Asian woman, two well-circumscribed nodules in the left lung and multiple thin-walled, irregularly shaped cysts on the basal and medial area of the lungs were disclosed by chest roentgenogram and computer-assisted tomography (CT) during a preoperative survey for a bilateral faucial tonsillectomy. Analysis of the resected tumor showed large polygonal cells with clear cytoplasm proliferating in a solid pattern. Immunohistochemistry revealed that these tumor cells were positive for microphthalmia-transcription factor, S100, and CD1a but negative for HMB45, indicating that the tumor was a CCST. Genetic testing indicated that the patient had a germline mutation on exon 12 of the FLCN gene, i.e., insertion of 7 nucleotides (CCACCCT) (c.1347_1353dupCCACCCT). Direct sequencing of the FLCN exon 12 using genomic DNA obtained from her microdissected CCST cells clearly revealed loss of the wild-type FLCN sequence, which confirmed complete functional loss of the FLCN gene. On the other hand, no loss of heterozygosity around TCS1- or TSC2-associated genetic region was demonstrated. Conclusion: To our knowledge, this is the first report of CCST of the lung in a patient with BHDS, indicating that CCST should be added to the spectrum of pulmonary manifestations of BHDS. [ABSTRACT FROM AUTHOR]

Rheum palmatum L. (RP) has been widely used in traditional medicine for the treatment of various diseases in Asian countries. The molecular mechanism of its anti-metastasis effect remains elusive. The present study assessed the effect of RP ethanol extract (RPE) on the highly metastatic human MDA-MB-231 breast cancer cells in vitro . At a non-toxic concentration, RPE inhibited migration, motility and invasion in a concentration-dependent manner. To investigate the mechanisms involved, real-time PCR and Western blot analyses were performed. Results showed that RPE down-regulated the levels of extracellular matrix degradation-associated proteins, including MMP-2/-9, uPA and uPAR, and up-regulated PAI-1. In addition, RPE affected NF-κB by degrading IkBα, and affected the mitogen-activated protein kinase signal transduction pathway by depressing the activation of p38, ERK and Akt. These results suggest that RPE has potential anti-metastatic activity and warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the major malignant diseases worldwide, especially in Asia, and Japan and Korea have the highest incidence in the world. Because most of the cases that are refractory to therapies die due to peritoneal dissemination (PD) of the cancer cells, controlling PD is important for patient survival. GSDMB is a member of the gasdermin gene family. Because GSDMB is expressed in many types of cancer, including GC, it is likely that the gene contains a regulatory region that is utilized for therapy of occult PD through cancer cell-specific expression of cytotoxic genes. Methods: We performed reporter assays to identify the regulatory region for the cancer cell-specific expression. We also constructed a lentiviral therapeutic vector that expresses herpes simplex virus thymidine kinase (HSVtk) in a GC cell-specific manner, and tested it in a mouse model of PD. Results: We identified the regulatory region at +496 to +989 from the GSDMB transcription start site and designated it as a GSDMB enhancer. The lentiviral therapeutic vector suppressed proliferation of a GC cell line, 60As6, in vitro in the presence of ganciclovir, and intraperitoneal administration of the vector prolonged the survival term of mice that were intraperitoneally inoculated with 60As6 one week prior to the administration. Conclusions: The GSDMB-driven HSVtk expression vector had a therapeutic effect on the occult PD model mice. This strategy can potentially be used to treat GC patients with PD. [ABSTRACT FROM AUTHOR]