Stem Cell Clinic

Vitro Biopharma Strengthens and Expands Its Distribution Agreement With Neuromics

GOLDEN, Colo., July 24, 2012 (GLOBE NEWSWIRE) -- Vitro Diagnostics, Inc. (VODG), dba Vitro Biopharma, announced an expanded relationship with a key distributor of its stem cell-based products, privately-held Neuromics, Inc (www.neuromics.com). Vitro Biopharma officials recently met Neuromics principals at their corporate headquarters in Minneapolis, MN. Neuromics was formed in 2005 by Pete Shuster, a marketing and sales professional with extensive experience in the computer industry who is now focused on providing integral products to the life science industry. Neuromics competitive advantage is based on providing products that lower costs and raise the probability of successful outcomes and include bio-markers, growth factors, transfection reagents, apoptosis detection kits, primary cells and related media. They are designed to serve basic and drug discovery researchers focusing on finding root causes and therapies for neuro-degenerative, autoimmune, inflammatory response diseases and certain forms of cancer.

Vitro Biopharma and Neuromics recently entered a distribution agreement whereby Vitro provides its stem cell-based products to Neuromics' customers. Stem cell research continues to grow, based on positive results from several studies showing potential clinical benefit of stem cell-based cellular therapy. There is a growing demand for adult stem cells known as mesenchymal stem cells (MSCs). Vitro Biopharma manufactures and sells several fundamental tools needed to advance adult stem cell research and clinical studies, including human MSCs and derivatives, the MSC-Gro(TM) Brand of media optimized for growth and differentiation of MSCs as well as assay kits for determination of MSC quality, potency and response to toxic agents.

Based on the growing demand for MSC products provided by Vitro Biopharma for both research and clinical studies, Neuromics officials have committed increased resources to promote these products. Furthermore, both Vitro Biopharma and Neuromics are evaluating additional products that are perceived to enhance the competitive advantage of Vitro Biopharma's existing MSC product line through strategic combination. A strategic goal moving forward, is an additional partner to supply devices needed for FDA-compliant manufacture of clinical materials for use in pre-clinical and clinical studies. These devices are known as bio-reactors that allow for highly controlled and reproducible production of large numbers of stem cells needed to provide therapeutic benefit. Several characteristics of these bioreactors are essential in reaching the demanding goals needed to achieve regulatory compliant manufacturing to support stem cell therapy that maintains rigorous standards of safety and efficacy. We are presently evaluating suitable devices for this application that appear to be well-suited to the required needs, specifications and characteristics.

Dr. Jim Musick, Vitro's President & CEO, said, "We are very pleased to expand our relationship with Neuromics, Inc and look forward to a long-term mutually beneficial business relationship. While we focus on product development, manufacturing and advancement of our product pipeline, our sales partnerships are important alliances in the expansion of revenue generation. Neuromics is an ideally suited sales partner due to their broad experience and success in distribution of critical life science products. We also see the importance of a complete manufacturing system to support stem cell-based cellular therapy. It is through the highly complex interactions of cells, cell culture media, extracellular matrices and other environmental conditions that together determine the characteristics of the stem cells intended for clinical use. We also anticipate additional expansion of our relationship with Neuromics as Vitro Biopharma's product pipeline advances through the commercialization process."

"Neuromics' strategic direction aligns tightly with Vitro's goal of 'Harnessing the Power of Cells(TM)'", said Shuster, "expanding capabilities enable us to serve an increasing segment of the Biotech and Pharma research community. This is especially true of the stem cell and regenerative medicine research community. Our relationship with Vitro Biopharma adds horsepower to these capabilities. Mesenchymal Stem Cells and Media are raw materials for high throughput and high content cell-based assays. Better materials help insure only the best targets, biologicals and compounds are passed on to downstream processes."

About Vitro Diagnostics, Inc.

Vitro Diagnostics, Inc. dba Vitro Biopharma (VODG);(http://www.vitrobiopharma.com), owns U.S. patents for production of FSH, immortalization of pituitary cells, and a cell line that produces beta islets for use in treatment of diabetes. Vitro also owns a pending international patent for generation of pluripotent stem cells. Vitro's mission is "Harnessing the Power of Cells(TM)" for the advancement of regenerative medicine to its full potential. Vitro operates within a modern biotechnology manufacturing, R&D and corporate facility in Golden, Colorado. Vitro manufactures and sells "Tools for Stem Cell and Drug Development(TM)", including human mesenchymal stem cells and derivatives, MSC-Gro(TM) optimized media for stem cell self-renewal and lineage-specific differentiation. Vitro recently formed a strategic alliance with HemoGenix(R), Inc. (http://www.hemogenix.com/) to jointly manufacture and distribute LUMENESC(TM) and LumiSTEM(TM) quantitative assays for determination of stem cell quality, potency and response to toxic agents.

About Neuromics, Inc.

Neuromics (http://www.neuromics.com), located in Minneapolis, MN, is a profitable and growing bio-regents company. The company was initially built by supplying bio-markers to Neuroscience Researchers. Today, Neuromics provides a range of solutions that include markers, growth factors, gene expression analysis tools, apoptosis detection kits, primary cells and related media. These solutions are increasingly being used in combinations by customers to help accelerate or improve the process of drug discovery.

Safe Harbor Statement

Link:
Vitro Biopharma Strengthens and Expands Its Distribution Agreement With Neuromics

Fort Myers doctor rejects settlement in stem cell case in which patient died

K.K.Yankopolus

Photo by Allie Garza

Dr. Zannos Grekos, a cardiologist whose practice is in Bonita Springs, speaks with a seminar attendant after one of his educational seminars about stem cell treatment, using one's own stem cells, for treating heart disease and other medical conditions, on Monday, March 14, 2011, at the Collier County Library. Allie Garza/Staff

FORT MYERS A Fort Myers physician has rejected a settlement agreement with state regulators over his role in a stem cell treatment with a patient who later died.

The deal that Dr. Konstantine Yankopolus turned down had him paying a fine of $25,000 and the state Department of Health's case expenses of $12,200. He would have been on probation for two years with another physician indirectly supervising him.

Yankopolus, who has a primary-care practice in Fort Myers, assisted Dr. Zannos Grekos in March with the controversial stem cell treatment on a 77-year-old Indiana man, according to state reports.

Now that Yankopolus has rejected the settlement terms, which would have needed approval of the state Board of Medicine, the state is reopening its complaint against him. An administrative hearing that had been canceled when the settlement was in the works will be scheduled again.

Yankopolus declined to comment about his decision to reject the deal and take his chances with what an administrative law judge may recommend for discipline. His license is now restricted he is prohibited from doing anything with stem cells.

The patient, Richard Poling, was seeking treatment for pulmonary hypertension and went into cardiac arrest in Grekos' Bonita Springs practice and died later at a hospital.

Grekos was under a state order not to do anything with stem cells because of his similar treatment of an earlier patient, a 66-year-old breast cancer survivor. She died from her injuries after she fell in her home hours after the procedure.

Read more here:
Fort Myers doctor rejects settlement in stem cell case in which patient died

Stem Cell Therapy: Cure For Autism?

By ANGELO G. GARCIA

MANILA, Philippines Parents of children with autism, or other developmental condition for that matter, go to great lengths to find a cure for their children. Even though these may not exist yet for most conditions, parents exhaust all possible means to look for ways to improve the lives of their children.

For some parents, the cost of these cures is of no question.

For instance, Janise Tang Piap immediately took charge of the situation upon learning that her son, Ethan, has autism. Janise turned to a battalion of doctors and therapists and even attended several conferences to understand her son's condition and how to improve it.

I took charge. I researched, I attended conferences. I was like a mad scientist, she recalls. Of course, the more important thing for a parent is to accept the fact that your child does have disability before you take charge.

MAD SCIENTIST

Janise did not stop at therapies though and proceeded to do further research until she came upon stem cell therapy that are being done in South America and China. She went as far as saving the umbilical cord blood cells of her second baby who was born in 2009, thinking that someday, this could be useful in the cure for autism.

Last year, she found out about Villa Medica, a clinic in Edenkoben, Germany that specializes in stem cell treatment for various conditions such as Parkinson's disease, diabetes Mellitus and autism.

Without missing a beat, Janise decided that stem cell therapy could help Ethan and they went on with the procedure.

Today, a year after the procedures, Janise is more than happy at the results, at improvements she never dreamt of happening to her son who is now nine years old.

Continued here:
Stem Cell Therapy: Cure For Autism?

Stem cell treatment for the heart ready for Phase II clinical trials (Weekend Rounds)

A review of life science current events reported by MedCity News this week.

Stem cell treatment for ischemia, heart failure raises enough for clinical trials. The regenerative medicine company Juventas Therapeutics, which had already said it added Takeda Pharmaceuticals to its roster of investors, said this weekend it has raised enough money to take its treatments for heart failure and a severe form of peripheral artery disease through its latest round of clinical trials.

CEO: $270M acquisition of US Endoscopy is STERIS most significant dealin many years. While STERIS has not historically had a presence in the procedural area of gastrointestinal endoscopy focusing instead on reprocessing products like soaks and scrubs Rosebrough said the integration of US Endoscopys portfolio of bleed management, retrieval and other GI-related devices is directly aligned with the companys strategy to target growing markets around its core products.

Ohio business leader Baiju Shah to depart BioEnterprise for biotech investment fund. Shah, the founder and longtime CEO of BioEnterprise, will join BioMotiv, the for-profit side of the $250 million Harrington Project for Discovery & Development housed at University Hospitals Case Medical Center, as CEO.

Pain device maker Neuros Medicals $3.5M round led by Boston Scientific, Glengary. The companys device, called the Electrical Nerve Block, comprises a pacemaker-sized generator and a lead that wraps around a peripheral nerve, and delivers stimulation to block pain. The four-year-old company will use the money to add staff and continue testing of the Electrical Nerve Block, it said in a statement.

Original post:
Stem cell treatment for the heart ready for Phase II clinical trials (Weekend Rounds)

The Yin and Yang of Stem Cell Quiescence and Proliferation

Newswise KANSAS CITY, MO Not all adult stem cells are created equal. Some are busy regenerating worn out or damaged tissues, while their quieter brethren serve as a strategic back-up crew that only steps in when demand shoots up. Now, researchers at the Stowers Institute for Medical Research have identified an important molecular cue that keeps quiescent mouse hematopoietic (or blood-forming) stem cells from proliferating when their services are not needed.

Publishing in the July 20, 2012 issue of Cell, the team led by Stowers Investigator Linheng Li, Ph.D., report that Flamingo and Frizzled 8, a tag team best known for its role in establishing cell polarity, are crucial for maintaining a quiescent reserve pool of hematopoietic stem cells in mouse bone marrow. Their finding adds new insight into the mechanism that controls the delicate balance between long-term maintenance of stem cells and the requirements of ongoing tissue maintenance and regeneration.

Hematopoietic stem cells daily produce billions of blood cells via a strict hierarchy of lineage-specific progenitors, says Li. Identifying the molecular signals that allow hematopoietic stem cell populations to sustain this level of output over a lifetime is fundamental to understanding the development of different cell types, the nature of tumor formation, and the aging process. My hope is that these insights will help scientists make meaningful progress towards new therapies for diseases of the blood.

The current working model, which grew out of earlier work by Li and others, postulates that hematopoietic stem cells (HSC), which are part of the reserve pool sit quietly and only divide a few times a year. They jump into action only when needed to replace active HSCs damaged by daily wear and tear or to increase their numbers in response to injury or disease. But how quiescent and active hematopoietic stem cell subpopulations are maintained and regulated in vivo is largely unknown.

What is known is that both populations of cells reside in adjacent specialized microenvironments, which provide many of the molecular cues that guide stem cell activity. Frequently cycling HSCs constitute around 90 percent of all hematopoietic stem cells and are found in the central marrow, where they seek the company of endothelial and perivascular cells. The main home base of quiescent hematopoietic stem cells is trabecular bone, the spongy part typically found at the end of long bones. Here, these cells engage in a constant molecular dialog with preosteoblasts, the precursors of bone-forming osteoblasts, which are characterized by the expression of N-cadherin.

Trying to decode the nature of the conversation graduate student and first author Ryohichi Sugimura focused on Flamingo (Fmi), a surface-based adhesion molecule, and Frizzled 8 (Fz8), a membrane-based receptor. Both molecules are part of the non-canonical arm of the so-called Wnt signaling pathway, a large network of secreted signaling molecules and their receptors. The canonical arm of the Wnt-signaling pathway exerts its influence through beta-catenin and helps regulate stem cell self-renewal in the intestine and hair follicles.

After in vitro experiments had revealed that Fmi and Fz8 accumulate at the interface between co-cultured quiescent hematopoietic stem cells and preosteoblasts, Sugimura and his colleagues were able to show that Fmi also regulates Fz8 distribution in vivo. This observation provided the first hint that these cooperation partners may carry at least part of the conversation that instructs hematopoietic stem cells to sit still. It also confirmed the previous finding by Lis team that a portion of HSCs resides in the N-cadherin+ osteoblastic niche.

When Sugimura examined the expression patterns of individual members of the Wnt signaling network within quiescent HSCs microenvironment he found that levels of canonical Wnt ligands where low. Levels of non-canonical Wnt ligands and inhibitors of the canonical arm of the Wnt signaling network, on the other hand, were high.

These observations indicated that the osteoblast niche provides a microenvironment in which non-canonical Wnt signaling prevails over canonical Wnt-signaling under normal conditions, says Sugimura. It also suggested that Fmi and Fz8 may play a direct role in maintaining the pool of quiescent hematopoietic stem cells.

Mice that had been genetically engineered to lack either Fmi or Fz8 provided the crucial clue: Not only had the number of quiescent hematopoietic stem cells plummeted in these mice, their hematopoietic stem cell function was reduced by more than 70 percent as well.

Follow this link:
The Yin and Yang of Stem Cell Quiescence and Proliferation

Stem cell procurement plan gets ministry OK

A health ministry panel will allow cord blood banks to provide raw material to create induced pluripotent stem cells for regenerative medicine, a move that would boost the establishment of an "iPS Stock" system proposed by Kyoto University professor Shinya Yamanaka.

Only cord blood not used in leukemia treatment would be provided to the iPS Stock for use in creating iPS cells, said the members of the panel under the Ministry of Health, Labor and Welfare.

The details of conditions for the provision will be discussed by eight banks storing cord blood and Kyoto University, the members said.

In a related move, Yamanaka said Tuesday he aims to team up with the Japanese Red Cross Society in the hope that by allowing scientists to tap into the society's data on human leukocyte antigen types, which can be compared with blood types for cells, the iPS Stock would be able to promptly procure the types of cells unlikely to be rejected by transplant recipients.

Establishing the iPS Stock would help physicians to shorten the time and reduce the costs associated with procuring cells for transplant treatment. But as patients would be receiving other people's cells, it is necessary to work on steps to reduce rejection.

Because only 1 in 1,000 has HLA types unlikely to cause rejection, collecting several dozen of the rare types would enable physicians to cover around 80 percent of the Japanese population.

A likely challenge, however, is to create a new system to secure donors' consent regarding the use of the banks, originally intended for the treatment of diseases such as leukemia, for the iPS Stock.

An advantage of using the banks is that blood and bone marrow stored by the banks run by the Red Cross and other organizations have had their HLA types checked prior to registration, making it easier for medical personnel to find the desired blood with rare properties.

This compares with soliciting volunteers to provide blood, which entails checking around 200,000 samples for the desired types, at enormous cost.

The rest is here:
Stem cell procurement plan gets ministry OK

Cytomedix Announces Collaboration With Duke University on Phase I Clinical Study of ALD-451 in Malignant Glioma

GAITHERSBURG, MD--(Marketwire -07/18/12)- Cytomedix, Inc. (CMXI) (the "Company"), a regenerative therapies company commercializing and developing innovative platelet and adult stem cell technologies, announces the initiation of a Phase I clinical study with ALD-451 in brain cancer patients in collaboration with Duke University Medical Center.

The open-label study will enroll up to 12 patients and is intended to demonstrate the feasibility and safety of ALD-451 when administered intravenously in World Health Organization ("WHO") grade IV malignant glioma patients following surgery, radiation therapy and treatment with temozolomide. The trial also will obtain an initial description of the effects of ALD-451 on neuro-cognition. The clinical study is open for enrollment having received Investigational New Drug clearance from the U.S. Food and Drug Administration and Investigational Review Board clearance from Duke University Medical Center(ClinicalTrials.gov Identifier: NCT01639612).

The study's principal investigator is Dr. Annick Desjardins, Assistant Professor of Medicine at The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center. Co-investigators are Dr. Henry S. Friedman, Deputy Director, The Preston Robert Tisch Brain Tumor Center and Dr. Joanne Kurtzberg, Chief Scientific Officer and Medical Director, Robertson Clinical & Translational Cell Therapy Program. Cytomedix will be responsible for manufacturing ALD-451 for the clinical trial. Duke University Medical Center, through the Robertson Clinical & Translational Cell Therapy Program, will fund the trial and be responsible for all other aspects of the study.

"We are excited to initiate patient recruitment in this study and to explore the use of this cellular therapy to treat the neuro-cognitive side effects of treating these devastating cancers," said Dr. Desjardins.

Martin P. Rosendale, Chief Executive Officer of Cytomedix, stated, "We are delighted to be working on this important trial with leading clinicians at Duke University Medical Center, one of the world's leading brain cancer centers for both treatment and research. Malignant glioma patients who undergo surgery, radiation therapy and temozolomide treatment oftentimes experience deterioration of neuro-cognition and have poor patient-reported outcomes. Earlier studies suggest that ALDH bright cells may repair neural brain damage. We expect this study to corroborate those results and look forward to advancing the development of this very promising product candidate."

About Malignant Glioma Primary central nervous system ("CNS") tumors represent about 1.35% of all cancers and 2.2% of all cancer-related deaths. Glial neoplasms represent about 40% of all primary CNS tumors and about 75% are malignant. Malignant gliomas include WHO grade III: anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma, and WHO grade IV: glioblastoma and gliosarcoma. Because of their extensive infiltrative and invasive nature, malignant gliomas present unique challenges. This infiltrative nature, combined with their proximity to critical intracranial structures as well as operative difficulty distinguishing between normal and neoplastic cells, significantly reduces the efficacy of surgical resection. Radiation therapy and systemic chemotherapy are necessary adjuncts to treatment. Children and adults who receive radiation therapy involving the brain frequently experience a progressive cognitive decline, significantly affecting their quality of life.

About ALD-451ALD-451 is the population of autologous pluri-potent ALDHbr stem cells isolated from the patients' bone marrow using Cytomedix' proprietary technology. These adult stem cells express high levels of the enzyme ALDH, an indicator of biological activity in heterogenous early stage stem cells. Preclinical research with ALD-451 bright cells suggests that they may promote the repair of tissue damage. Recently, preliminary data presented at the 2012 International Society of Cell Therapy showed that ALDHbr bright cells reduced severity of intracranial inflammation after brain irradiation in an animal model. Investigators have also completed preclinical research that showed improvements in motor function, improvements in the slowing of decrease in brain volume, the reversal of decline in stroke-induced cell viability and improved blood flow, or perfusion, in the brain.

About Cytomedix, Inc. Cytomedix, Inc. is an autologous regenerative therapies company commercializing innovative platelet technologies for orthopedics and wound care with a pipeline of adult stem cell therapies for tissue repair. The Company markets the AutoloGel System, a device for the production of autologous platelet rich plasma ("PRP") gel for use on a variety of exuding wounds and the Angel Whole Blood Separation System, a blood processing device and disposable products used for the separation of whole blood into red cells, platelet poor plasma ("PPP") and PRP in surgical settings. On February 8, 2012 Cytomedix closed the acquisition of Aldagen, a biopharmaceutical company developing regenerative cell therapies based on its proprietary ALDH bright cell ("ALDHbr") technology, currently in a Phase 2 trial for the treatment of ischemic stroke. For additional information please visit http://www.cytomedix.com

Safe Harbor StatementStatements contained in this press release not relating to historical facts are forward-looking statements that are intended to fall within the safe harbor rule for such statements under the Private Securities Litigation Reform Act of 1995. The information contained in the forward-looking statements is inherently uncertain, and Cytomedix' actual results may differ materially due to a number of factors, many of which are beyond Cytomedix' ability to predict or control, including among many others, risks and uncertainties related to the Company's ability to successfully integrate the Aldagen acquisition, to successfully manage contemplated clinical trials, to manage and address the capital needs, human resource, management, compliance and other challenges of a larger, more complex and integrated business enterprise, viability and effectiveness of the Company's sales approach and overall marketing strategies, commercial success or acceptance by the medical community, competitive responses, the Company's ability to raise additional capital and to continue as a going concern, and Cytomedix's ability to execute on its strategy to market the AutoloGel System as contemplated. To the extent that any statements made here are not historical, these statements are essentially forward-looking. The Company uses words and phrases such as "believes," "forecasted," "projects," "is expected," "remain confident," "will" and/or similar expressions to identify forward-looking statements in this press release. Undue reliance should not be placed on forward-looking information. These forward-looking statements are subject to known and unknown risks and uncertainties that could cause actual events to differ from the forward-looking statements. More information about some of these risks and uncertainties may be found in the reports filed with the Securities and Exchange Commission by Cytomedix, Inc. Cytomedix operates in a highly competitive and rapidly changing business and regulatory environment, thus new or unforeseen risks may arise. Accordingly, investors should not place any reliance on forward-looking statements as a prediction of actual results. Except as is expressly required by the federal securities laws, Cytomedix undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, changed circumstances or future events or for any other reason. Additional risks that could affect our future operating results are more fully described in our U.S. Securities and Exchange Commission filings, including our Annual Report for the year ended December 31, 2011 and other subsequent filings. These filings are available at http://www.sec.gov.

Read the original:
Cytomedix Announces Collaboration With Duke University on Phase I Clinical Study of ALD-451 in Malignant Glioma

Mechanisms that allow embryonic stem cells to become any cell in the human body identified

ScienceDaily (July 18, 2012) New research at the Hebrew University of Jerusalem sheds light on pluripotency -- the ability of embryonic stem cells to renew themselves indefinitely and to differentiate into all types of mature cells. Solving this problem, which is a major challenge in modern biology, could expedite the use of embryonic stem cells in cell therapy and regenerative medicine.

If scientists can replicate the mechanisms that make pluripotency possible, they could create cells in the laboratory which could be implanted in humans to cure diseases characterized by cell death, such as Alzheimer's, Parkinson's, diabetes and other degenerative diseases.

To shed light on these processes, researchers in the lab of Dr. Eran Meshorer, in the Department of Genetics at the Hebrew University's Alexander Silberman Institute of Life Sciences, are combining molecular, microscopic and genomic approaches. Meshorer's team is focusing on epigenetic pathways -- which cause biological changes without a corresponding change in the DNA sequence -- that are specific to embryonic stem cells.

The molecular basis for epigenetic mechanisms is chromatin, which is comprised of a cell's DNA and structural and regulatory proteins. In groundbreaking research performed by Shai Melcer, a PhD student in the Meshorer lab, the mechanisms which support an "open" chromatin conformation in embryonic stem cells were examined. The researchers found that chromatin is less condensed in embryonic stem cells, allowing them the flexibility or "functional plasticity" to turn into any kind of cell.

A distinct pattern of chemical modifications of chromatin structural proteins (referred to as the acetylation and methylation of histones) enables a looser chromatin configuration in embryonic stem cells. During the early stages of differentiation, this pattern changes to facilitate chromatin compaction.

But even more interestingly, the authors found that a nuclear lamina protein, lamin A, is also a part of the secret. In all differentiated cell types, lamin A binds compacted domains of chromatin and anchors them to the cell's nuclear envelope. Lamin A is absent from embryonic stem cells and this may enable the freer, more dynamic chromatin state in the cell nucleus. The authors believe that chromatin plasticity is tantamount to functional plasticity since chromatin is made up of DNA that includes all genes and codes for all proteins in any living cell. Understanding the mechanisms that regulate chromatin function will enable intelligent manipulations of embryonic stem cells in the future.

"If we can apply this new understanding about the mechanisms that give embryonic stem cells their plasticity, then we can increase or decrease the dynamics of the proteins that bind DNA and thereby increase or decrease the cells' differentiation potential," concludes Dr. Meshorer. "This could expedite the use of embryonic stem cells in cell therapy and regenerative medicine, by enabling the creation of cells in the laboratory which could be implanted in humans to cure diseases characterized by cell death, such as Alzheimer's, Parkinson's, diabetes and other degenerative diseases."

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

More here:
Mechanisms that allow embryonic stem cells to become any cell in the human body identified