CD11b activators(integrin subunit alpha M activators), CD32A activators(Low affinity immunoglobulin gamma Fc region receptor II-a activators), Immunostimulants

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Breast Cancer

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaKRAS Wild-type Colorectal CancerMelanoma, Cutaneous Malignant+ [2]

Originator Organization

Biothera Pharmaceuticals, Inc. (Delaware)

Active Organization

Hibercell, Inc.Startup

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Clinical Trials associated with PGG glucan

NCT05484011 / TerminatedPhase 1

P1b, Open-Label, Safety, Tolerability, Efficacy Study of a Soluble Beta-glucan Odetiglucan in Combination w/ a CD40 Agonist (CDX-1140) in Patients w/ Metastatic Pancreatic Adenocarcinoma Whose Disease Did Not Progress During 1st-Line Chemo

The primary objective of this maintenance therapy study is to identify the maximum tolerated dose (MTD) and/ or recommended Phase 2 dose (RP2D), and evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of odetiglucan in combination with CDX-1140 in patients with metastatic PDAC with evidence of response or stable disease following a minimum of 16 and no more than 32 weeks of chemotherapy.
Up to 45 patients will be enrolled and dosed (30 patients in Part A and 15 in Part B).

Start Date15 Dec 2022

Sponsor / Collaborator

Hibercell, Inc.Startup

[+1]

NCT05159778 / CompletedPhase 2

A Multicenter, Open-label, Phase 2 Study of Imprime PGG and Pembrolizumab in Patients With Metastatic Breast Cancer (mBCA) Who Have Progressed Through Prior Hormonal Therapy

The primary objective of this Phase 2 Simon 2-Stage study is to determinate the Overall Response Rate (ORR) per RECIST v1.1 following treatment with Imprime PGG + pembrolizumab in patients with ER/PR+/ HER2(-) metastatic breast cancer who have progressed through prior hormone therapy with at least one CDK4/6 inhibitor, and a maximum of 2 subsequent chemotherapy treatment. Patients will be screened for baseline anti-β glucan antibody level (ABA; measured in peripheral blood). Those patients with an ABA greater than or equal to 20 mcg/ml and meeting all other I/E criteria, will be enrolled.
The study will enroll 47 patients with 23 patients enrolled into Stage 1. If 4 or more patients in Stage 1 have an objective response after 12 weeks of treatment, the study will proceed into Stage 2. A total of 24 patients will be enrolled in Stage 2 for a total combined population of 47. Overall, objective responses must be observed in 10 patients for the study to be declared a success.

Start Date09 Nov 2021

Sponsor / Collaborator

Hibercell, Inc.Startup

[+1]

CTRI/2021/10/037380 / Not yet recruitingPhase 3

An Open Label, Prospective, Randomized, Comparative, Multiple Arm Clinical Study to Evaluate the Immunomodulatory Efficacy of Nichi Glucan in Comparison with Conventional Therapeutic Regimen in Adult Subjects with Covid-19 caused by SARS-COV2 (B-COV)

Start Date25 Oct 2021

Sponsor / Collaborator-

100 Clinical Results associated with PGG glucan

100 Translational Medicine associated with PGG glucan

100 Patents (Medical) associated with PGG glucan

265

Literatures (Medical) associated with PGG glucan

01 Oct 2024·Small

Dual‐Drug Nanomedicine Assembly with Synergistic Anti‐Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization

Article

Author: Zhou, Wen Hu ; Zu, Hong Lin ; Zhuang, Pei Pei ; Wang, Hai Yang ; Peng, Chao ; Peng, Ying ; Yao, Ye ; Zhu, Zi Jia ; Peng, Cheng ; Yue, Jie ; Wang, Qing Shan

AbstractAbdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal–organic‐framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1‐to‐M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

01 May 2024·International Journal of Biological Macromolecules

Discovery of a botanical compound as a broad-spectrum inhibitor against gut microbial β-glucuronidases from the Tibetan medicine Rhodiola crenulata

Article

Author: Huang, Jian ; Ge, Guang-Bo ; Zhang, Ya-Ni ; Zhu, Guang-Hao ; Zhang, Shou-De ; Ma, Li-Juan ; Guo, Zhao-Bin ; Hou, Jie ; Hou, Xu-Dong ; Chen, Lu ; Sun, Jian-Ming

Gut microbial β-glucuronidases (gmβ-GUS) played crucial roles in regulating a variety of endogenous substances and xenobiotics on the circulating level, thus had been recognized as key modulators of drug toxicity and human diseases. Inhibition or inactivation of gmβ-GUS enzymes has become a promising therapeutic strategy to alleviate drug-induced intestinal toxicity. Herein, the Rhodiola crenulata extract (RCE) was found with potent and broad-spectrum inhibition on multiple gmβ-GUS enzymes. Subsequently, the anti-gmβ-GUS activities of the major constituents in RCE were tested and the results showed that 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) acted as a strong and broad-spectrum inhibitor on multiple gmβ-GUS (including EcGUS, CpGUS, SaGUS, and EeGUS). Inhibition kinetic assays demonstrated that PGG effectively inhibited four gmβ-GUS in a non-competitive manner, with the K_i values ranging from 0.12 μM to 1.29 μM. Docking simulations showed that PGG could tightly bound to the non-catalytic sites of various gmβ-GUS, mainly via hydrogen bonding and aromatic interactions. It was also found that PGG could strongly inhibit the total gmβ-GUS activity in mice feces, with the IC₅₀ value of 1.24 μM. Collectively, our findings revealed that RCE and its constituent PGG could strongly inhibit multiple gmβ-GUS enzymes, suggesting that RCE and PGG could be used for alleviating gmβ-GUS associated enterotoxicity.

01 Apr 2024·Combinatorial Chemistry & High Throughput Screening

Osteoblast Biospecific Extraction Conjugated with HPLC Analysis for Screening Bone Regeneration Active Components from Moutan Cortex

Article

Author: Yao, Fei ; Chen, Wei ; Gu, Weiwei ; Xu, Heng ; Liang, Guoqiang ; Hou, Wenyue ; Jiang, Guorong ; Zhang, Lurong ; Zhang Zhu, Ruixian

Introduction:The function of promoting bone regeneration of Moutan Cortex (MC), a traditional Chinese medicine, has been widely known but, the effective components of MC in promoting osteoblast-mediated bone regeneration were still unclear.Objective:The method of osteoblast membrane bio-specific extraction conjugated with HPLC analysis was established to screen bone regeneration active components from MC.Methods:The fingerprints, washing eluate and desorption eluate of MC extract were analyzed by the established HPLC-DAD method. The established MC3T3-E1 cells membrane chromatography method was used for the bio-specific extraction of MC. The isolated compounds were identified by MS spectrometry. The effects and possible mechanisms of the isolated compounds were evaluated by molecular docking, ALP activity, cell viability by MTT Assay and proteins expression by Western Blot Analysis.Results:The active compound responsible for bone regeneration from MC was isolated using the established method of osteoblast membrane bio-specific extraction conjugated with HPLC analysis, and it was identified as 1,2,3,4,6-penta-O-β-galloyl-D-glucose (PGG) by MS spectrometry. It was further demonstrated through molecular docking that PGG could fit well into the functional ALP, BMP2, and Samd1 binding pocket. The proliferation of osteoblasts was promoted, the level of ALP was increased, and the protein expression of BMP2 and Smad1 was increased as shown by further pharmacological verification.Conclusion:It was concluded that PGG, the bone regeneration active compound from MC, could stimulate the proliferation of osteoblasts to promote osteoblast differentiation, and its mechanism might be related to the BMP/Smad1 pathway.

News (Medical) associated with PGG glucan

23 Oct 2024

·www.biospace.com

HiberCell Receives FDA Fast Track Designation for HC-7366 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (AML)

BOSTON, Oct. 23, 2024 (GLOBE NEWSWIRE) -- HiberCell, Inc., a clinical-stage biotechnology company developing therapeutics to address advanced cancer and cancer resistance, is pleased to announce that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to HC-7366 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia. The FDA’s Fast Track program aims to facilitate the development, and expedite the review, of novel potential therapies that are designed to treat serious conditions and have the potential to address significant unmet medical need. “We are proud to announce the grant of Fast Track designation by the FDA,” said Jonathan Lanfear, President & CEO of HiberCell. Receiving Fast Track designation highlights the FDA’s recognition of the robust preclinical data generated to date for HC-7366 and the potential for HC-7366 to address the significant unmet need that exists in R/R AML.” Mr. Lanfear continued, “HC-7366 was the first GCN2-activator to enter the clinic in AML and is the only GCN2-targeting agent to receive Fast Track designation for the treatment of AML, validating our preclinical and translational efforts. We plan to leverage the Fast-Track designation to work closely with the FDA to facilitate and, potentially accelerate the development of HC-7366 in AML.” HC-7366 is currently under clinical investigation in both solid and liquid tumor settings. The Phase 1b study in AML (NCT06285890) will evaluate the safety, tolerability, and preliminary efficacy of HC-7366 in relapsed/refractory (R/R) AML or MDS AML. This study aims to determine the recommended Phase 2 dose (RP2D) of HC-7366 in a R/R AML population. Dependent on observations in the dose escalation portion, this study may include additional combination and monotherapy expansions. About HC-7366 HC-7366 is a first-in-class, first-in-human, selective, potent, small molecule activator of the general control nonderepressible 2 (GCN2) kinase. GCN2 is one of the kinases of the integrated stress response (ISR) family, which responds to amino acid deprivation and is a key metabolic stress sensor in cells. While cancer cells utilize the ISR for survival, prolonged or hyperactivation of GCN2 with HC-7366 has been shown to have antitumor and immunomodulatory activity as a monotherapy and in combination with standard of care agents in both solid and liquid tumor models. HC-7366 is currently under clinical development in a Phase 1b/2 study in clear cell renal cell carcinoma in combination with belzutifan (NCT06234605) and in a Phase 1b study in R/R AML (NCT06285890). About HiberCell HiberCell is a clinical stage oncology company, dedicated to the advancement of first-in-class agents with the novel MOA of modulation of adaptive stress pathways and antitumor immunity. We believe that therapeutic modulation of these mechanisms allows us to address advanced cancer and cancer resistance. Our product candidates HC-5404 and HC-7366, both having completed Phase 1a clinical trials, target the stress response kinases PERK and GCN2, respectively, while our product candidate odetiglucan, currently advancing towards Phase 2 clinical development, modulates the antitumor innate immune response. For more information about HiberCell, please visit hibercell.com. For Media/Investor Inquiries: IR@hibercell.com

Phase 1Fast TrackPhase 2

29 May 2024

·www.globenewswire.com

HiberCell Announces First Patient Dosed in Phase 1b Clinical Trial, Evaluating HC-7366 in Combination with Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia (AML)

May 28, 2024 -- HiberCell, Inc., a clinical-stage biotechnology company developing therapeutics to address advanced cancer and cancer resistance, is pleased to announce the first patient dosed in a clinical trial evaluating HC-7366 in combination with standard of care agents venetoclax and azacitidine for advanced acute myeloid leukemia (AML). "We are excited to announce the first patient dosed in this study," said Jonathan Lanfear, President & CEO of HiberCell. "This study builds on the preclinical data we have presented at recent conferences, including the 2023 ASH Annual Meeting and Exposition, which support evaluation of HC-7366 in combination with venetoclax and azacitidine in AML patients with significant unmet need." The study’s principal investigator is Dr. Abhishek Maiti, assistant professor of Leukemia at The University of Texas MD Anderson Cancer Center. Mr. Lanfear continued, "The initiation of this study along with our recently announced study of HC-7366 in clear cell renal cell carcinoma marks the continued advancement of HC-7366 and HiberCell. These are seminal combinatorial studies of HC-7366 with the potential to address large, targeted, and underserved patient populations. We look forward to seeing data for these studies throughout 2024 and 2025." The newly announced Phase 1b study (NCT06285890) will evaluate the safety, tolerability, and preliminary efficacy of HC-7366 in combination with standard dosing of venetoclax and azacitidine in patients with relapsed/refractory (R/R) AML or MDS AML. The study aims to determine the recommended Phase 2 dose (RP2D) of HC-7366 in combination with venetoclax and azacitidine in a R/R AML population. The study will enroll up to 18 patients. HC-7366 is a first-in-class, first-in-human, selective, potent, small molecule activator of the general control nonderepressible 2 (GCN2) kinase. GCN2 is one of the kinases of the integrated stress response (ISR) family, which responds to amino acid deprivation and is a key metabolic stress sensor in cells. While cancer cells utilize the ISR for survival, prolonged or hyperactivation of GCN2 with HC-7366 has been shown to have antitumor and immunomodulatory activity as a monotherapy and in combination with SOC agents in both solid and liquid tumor models. HC-7366 is currently under clinical development in a Phase 1b/2 study in clear cell renal cell renal cell carcinoma in combination with belzutifan (NCT06234605) and in a Phase 1b study in AML in combination with azacitidine and venetoclax (NCT06285890). HiberCell is a clinical stage oncology company, dedicated to the advancement of first-in-class agents with the novel MOA of modulation of adaptive stress pathways and antitumor immunity. We believe that therapeutic modulation of these mechanisms allows us to address advanced cancer and cancer resistance. Our product candidates HC-5404 and HC-7366, both having completed Phase 1a clinical trials, target the stress response kinases PERK and GCN2, respectively, while our product candidate odetiglucan, currently advancing towards Phase 2 clinical development, modulates the antitumor innate immune response. For more information about HiberCell, please visit hibercell.com. The content above comes from the network. if any infringement, please contact us to modify.

Clinical StudyPhase 2

02 May 2024

·www.globenewswire.com

HiberCell Announces First Patient Dosed in Clinical Collaboration with Merck, Evaluating HC-7366 in Combination with WELIREG® (belzutifan) in patients with advanced ccRCC

May 01, 2024 -- HiberCell, Inc., a clinical-stage biotechnology company developing therapeutics to address cancer relapse, metastasis, and resistance, is pleased to announce the dosing of the first patient in a Phase 1b study evaluating HC-7366, an activator of integrated stress response (ISR) Kinase GCN2, in combination with Merck’s oral hypoxia-inducible factor-2α (HIF-2α) inhibitor WELIREG® (belzutifan) for the treatment of advanced clear cell renal cell carcinoma (ccRCC). The Phase 1b study (NCT06234605) will evaluate the safety, tolerability, and preliminary efficacy of HC-7366 in combination with belzutifan in patients with advanced ccRCC. This trial will also determine a recommended Phase 2 dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd. Dose escalation of HC-7366 in the combination, followed by an expansion phase will optimize dose evaluation. An independent HC-7366 monotherapy cohort is being evaluated in parallel. The study will enroll up to 80 patients at clinical sites across the US. Robert J. Motzer, MD., Section Head, Kidney Cancer, Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center (MSK) will be the lead Principal Investigator (PI) for the clinical trial. "The first patient dosed in this trial marks the beginning of an exciting new chapter in the clinical development of HC-7366," stated Cherry Thomas, M.D., Chief Medical Officer. "The combination of HC-7366 with belzutifan, a key agent for the treatment of clear cell renal cell carcinoma, offers a potentially promising novel and differentiated treatment in a setting with major unmet need and limited treatment options for patients. We recently presented key aspects of the significant preclinical data in support of the combination at the 2024 American Association for Cancer Research Annual Conference." WELIREG® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. HC-7366 is a first-in-class, first-in-human, selective, potent, small molecule activator of the general control nonderepressible 2 (GCN2) kinase. GCN2 is one of the kinases of the integrated stress response (ISR) family, which responds to amino acid deprivation and is a key metabolic stress sensor in cells. While cancer cells utilize the ISR for survival, prolonged or hyperactivation of GCN2 with HC-7366 has been shown to have antitumor and immunomodulatory activity as a monotherapy and in combination with SOC agents in preclinical models of both solid and liquid tumors. HC-7366 is currently under clinical development in a Phase 1b study in clear cell renal cell carcinoma in combination with belzutifan. HiberCell is a clinical stage oncology company, dedicated to the advancement of first-in-class agents with the novel MOA of modulation of adaptive stress pathways and antitumor immunity. We believe that therapeutic modulation of these mechanisms allows us to address tumor metastasis, treatment resistance, and cancer relapse; all significant drivers of cancer-related deaths. Our product candidates HC-5404 and HC-7366, both having completed Phase 1a clinical trials, target the stress response kinases PERK and GCN2, respectively, while our product candidate odetiglucan, currently advancing towards Phase 2 clinical development, modulates the antitumor innate immune response. For more information about HiberCell, please visit hibercell.com. The content above comes from the network. if any infringement, please contact us to modify.

Phase 2AACR

100 Deals associated with PGG glucan

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Pancreatic Ductal Adenocarcinoma	Phase 2	US	Hibercell, Inc.Startup	15 Dec 2022
Pancreatic adenocarcinoma metastatic	Phase 2	US	Hibercell, Inc.Startup	15 Dec 2022
Breast Cancer	Phase 2	-	Hibercell, Inc.Startup	28 Apr 2022
Melanoma, Cutaneous Malignant	Phase 2	US	Hibercell, Inc.Startup	15 Aug 2021
KRAS Wild-type Colorectal Cancer	Phase 2	DE	Hibercell, Inc.Startup	01 Apr 2011
KRAS Wild-type Colorectal Cancer	Phase 2	FR	Hibercell, Inc.Startup	01 Apr 2011
KRAS Wild-type Colorectal Cancer	Phase 2	US	Hibercell, Inc.Startup	01 Apr 2011
KRAS Wild-type Colorectal Cancer	Phase 2	PR	Hibercell, Inc.Startup	01 Apr 2011
Advanced Lung Non-Small Cell Carcinoma	Phase 2	DE	Hibercell, Inc.Startup	01 Aug 2009
Advanced Lung Non-Small Cell Carcinoma	Phase 2	US	Hibercell, Inc.Startup	01 Aug 2009

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03003468 (BTCRC-LUN15-017, CTgov)	Phase 1/2	metastatic non-small cell lung cancer	35	Imprime PGG+pembrolizumab (Phase Ib)	dpltozmyli(vpumikofoa) = cajqywedoa lcamtdizlf (hqihdxjnlf, ijaixyxevy - imzqtccxsa) View more	-	13 Aug 2024
				PGG (Imprime PGG 4 mg/kg)	xjvanabkdw(wpmobicuwp) = baryetwnmo kngcfkpefp (tmbfznmagc, adhvyijnel - cesaqksira) View more
NCT02981303 (Phase 2 \| IMPRIME 1, CTgov)	Phase 2	Neoplasm Metastasis \| Triple Negative Breast Cancer \| Melanoma	64	Imprime PGG+pembrolizumab (Melanoma)	snryhvyvuu(gwdmzwswjs) = ajvuhlpcro omidmncatm (edfncdmztn, clkmsovfer - qggrhetros) View more	-	09 Jul 2024
				Imprime PGG+pembrolizumab (Triple Negative Breast Cancer)	snryhvyvuu(gwdmzwswjs) = opdsfiinxr omidmncatm (edfncdmztn, qrjoluobcq - kpytdelkcx) View more
NCT03555149 (MORPHEUS, CTgov)	Phase 1/2	Metastatic Colorectal Carcinoma	96	Regorafenib (Regorafenib (Control))	sokfurvoqq(jhhtdnycvh) = eghivwachs fyfnvlztfo (wtzeoaktsj, xzcygkibvw - ffxyhvqzot) View more	-	07 Nov 2023
				Imprime PGG+Atezolizumab+Bevacizumab (Atezolizumab + Imprime PGG + Bevacizumab)	sokfurvoqq(jhhtdnycvh) = qnntdizbmq fyfnvlztfo (wtzeoaktsj, lbewzhyvbq - hcrwyjrlbh) View more
NCT05159778 (ASCO2022)	Phase 2	Metastatic breast cancer	47	Odetiglucan 4 mg/kg/wk + Pembrolizumab 200 mg Q3wk	(aqjhnjnoml) = vioqzshwiv fmutddpmps (tlkcplznse ) View more	-	02 Jun 2022
NCT03003468 (BTCRC-LUN15-017, WCLC2021) Manual	Phase 1/2	Non-Small Cell Lung Cancer	35	Pembro+Imprime PGG (phase Ib)	(fciddshmmk) = surcqoscbc vprasuetuj (mlxlnrkzka, 1.28 - 27.8) View more	Negative	08 Sep 2021
				Pembro+Imprime PGG (phase II)	(fciddshmmk) = ecxftpnnht vprasuetuj (mlxlnrkzka, 1.35 - 5.13) View more
NCT03555149 (MORPHEUS, ASCO2021)	Phase 2	Metastatic Microsatellite Stable Colorectal Carcinoma	94	Atezolizumab + Imprime PGG + Bevacizumab	(opqpgdngrg) = xspswckqrf wlpkokhdqv (sbvgdvbuya, 4.4 - 10.5) View more	-	28 May 2021
				Regorafenib	(opqpgdngrg) = xggjusyhci wlpkokhdqv (sbvgdvbuya, 4.8 - NE) View more
NCT02086175 (CTgov)	Phase 2	Refractory Indolent Non-Hodgkin Lymphoma \| Recurrent Indolent Non-Hodgkin Lymphoma	25	Imprime PGG+Rituximab	socezrrntn(czhkpjvbqi) = dqinnhgfly lpknyshvnn (chmmsqhrsx, ogrdifpnbc - ixkudpdidb) View more	-	07 Jan 2021
NCT02981303 (IMPRIME 1, AACR2020)	Phase 2	Metastatic Triple-Negative Breast Carcinoma	44	Imprime PGG + Pembrolizumab	(vwedurwfbe) = iklnerskag vqiuecflgv (dekmmwpwmq, 7.9 - 29.4) View more	Positive	15 Aug 2020
NCT02981303 (Phase 2, SITC2020)	Phase 2	Metastatic melanoma	20	Imprime PGG (Imprime)	ezubckesrz(jztdtiorkc) = ysvzayatnq lovcussoek (wpkeqffxva ) View more	Positive	15 Apr 2020
NCT00874107 (Pubmed \| J Immunother Cancer) Manual	Phase 2	Non-Small Cell Lung Cancer First line	92	bevacizumab+carboplatin+paclitaxel+BTH1677	(enbzhnqesg) = tfkncgtuwg jgjpoftptx (nbwspmtqwz ) View more	Positive	27 Feb 2018
				bevacizumab+carboplatin+paclitaxel	(enbzhnqesg) = fupezlfhbf jgjpoftptx (nbwspmtqwz ) View more

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