Stem cell research for cystic fibrosis leaps forward

The fight against cystic fibrosis (CF) has taken a major step forward, with pioneering research by University of Adelaide scientists showing that cells causing the debilitating genetic disorder could be successfully replaced with healthy ones.

The research published in the journal Stem Cell Research and Therapy applies cell transplantation therapy, normally used in bone marrow transplants to treat immunodeficiency disorders.

“There are 70,000 people worldwide living with CF for which there is currently no cure, and disease in the lungs is the major cause of poor health and a significantly shortened life span,” says Dr Nigel Farrow, a Post-Doctoral Research Fellow from the University of Adelaide’s Robinson Research Institute, who conducted the study alongside Associate Professor David Parsons head of the research team based in the Women’s and Children’s Hospital.

In Australia, one in every 2,500 babies has CF, and one in 25 people carry the defective gene. Even though carriers are not affected by the disorder, they may pass the gene to their children. If both parents are carriers, each of their children has a 1 in 4 chance of being born with the disorder.

“Our research which applies stem cell transplantation, involves harvesting adult stem cells from the lungs of CF patients, correcting them with gene therapy, and then reintroducing those cells back into the patient,” says Dr Farrow.

“The new transplanted adult stem cells pass on their healthy genes to their ‘daughter cells’ providing a constant means to replenish the airways with healthy cells, and thereby combatting the onset of cystic fibrosis airway disease,” he said.

Working in mouse airways, the group successfully tested their new transplantation method, using a marker gene in place of the corrective CF gene in initial studies.

“The key to these successful transplantations was our innovative method; we first eliminated the existing surface cells, which then created the space required to introduce the new cells,” says Dr Farrow.

CF affects a person’s lungs and digestive system causing a build-up of mucus that seriously impairs their breathing and significantly increases the chances of chest infections.

Patients such as Nathan Rae are required to undergo a range of regular therapies to help to alleviate the symptoms of CF.

“I have intensive daily physiotherapy to clear my airways, eat a nutritious high-fat, high-calorie diet with lots of extra salt and vitamins, and take drugs that help me digest my food,” says Nathan.

“Exercise is really important, but as I regularly get chest infections, I have frequent hospital admissions, which inhibits my ability to exercise as much as I’d like,” he says.

This pioneering research demonstrates that, in principle, human airway stem cells can be transplanted into the lining of the lungs.

“If we can perfect this technique, it will accelerate this exciting research which could significantly improve the lives of those living with cystic fibrosis and potentially combat this chronic life-limiting illness,” says Dr Farrow.

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Story Source:

Materials provided by University of Adelaide. Note: Content may be edited for style and length.

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Journal Reference:

1. Nigel Farrow, Patricia Cmielewski, Martin Donnelley, Nathan Rout-Pitt, Yuben Moodley, Ivan Bertoncello, David Parsons. Epithelial disruption: a new paradigm enabling human airway stem cell transplantation. Stem Cell Research & Therapy, 2018; 9 (1) DOI: 10.1186/s13287-018-0911-4

https://bit.ly/2AGAivU

Muscle ‘switch’ may control the benefits of exercise

Some people respond well to both aerobic exercise and strength training, while others don’t. And some of us respond well to only one of those things, but not both. Scientists at Joslin Diabetes Center now have uncovered a surprising molecular “switch” that may help to explain why this happens.

“We’ve identified an exercise-activated biological pathway that hasn’t been studied at all,” says Sarah Lessard, PhD, an Assistant Investigator in Joslin’s section of Clinical, Behavioral and Outcomes Research and first author on a paper presenting the research in the journal Nature Communications.

Studying lab animals and humans, Lessard and her colleagues discovered that a protein called c-Jun N-terminal kinase (JNK)helps to drive response to exercise. If JNK is activated during exercise, the researchers say, that stimulates skeletal muscle growth. If it’s not activated, muscles improve their adaptation for endurance and aerobic capacity.

“It’s like a switch,” Lessard remarks. “If the switch is on, you’ll have muscle growth. If it’s turned off, you have endurance adaptation in the muscle.”

Exercise is a foundation for our overall health, and exercise that promotes aerobic capacity is a powerful factor in preventing diabetes, cardiovascular disease and other chronic metabolic diseases. However, that capacity is not evenly distributed among us.

“If a hundred people do the exact same aerobic training program, some will have huge improvements in aerobic capacity, and some will have little to no response,” Lessard notes. Her lab studies the biological signals that tell a muscle to adapt for aerobic capacity or for muscle growth.

In previous work, the Joslin team looked at which genes were activated in two groups of lab rats that had been bred for many generations to respond either very well or very poorly to endurance exercise training (running on treadmills). The scientists found that activation of the JNK biological pathway predicted that an animal would respond poorly to endurance exercise training.

That finding was a bit unexpected, since the researchers knew that JNK was associated with inflammation in metabolic diseases such as type 2 diabetes and obesity. So why would the protein be activated by exercise?

Lessard and her colleagues began their current study with mice that had been genetically modified to knock out production of JNK in their muscles. These “JNK knockout” mice remain perfectly healthy and will run vigorously on wheels in their cages very much like normal mice. (“Mice actually enjoy running several kilometers a night,” Lessard remarks.)

But when both groups of mice were trained to run, the investigators found the JNK knockout mice had a much higher increase than normal mice in aerobic exercise capacity, along with higher levels of blood vessels and of a type of muscle fiber specialized to give endurance.

Next, the Joslin researchers ran an experiment that promotes muscle growth in animals. Normal mice doubled the mass of their affected muscles, but the JNK knockout mice didn’t increase their muscle mass nearly as much.

Diving deeper into the biological mechanisms underlying these results, the scientists found that JNK works through a well-studied pathway involving myostatin, a protein that restrains muscle growth. Myostatin is targeted in some clinical trials that seek to increase muscle mass in aging and in diseases such as advanced cancer where muscle loss is often a serious problem.

The Joslin investigators then collaborated with Vernon Coffey, associate professor of exercise and sports science at Bond University in Gold Coast, Queensland, Australia, on tests in healthy, human volunteers. Results from Coffey’s group indicated that similar biological mechanisms were at work.

The tests showed that JNK was highly activated in the muscles of humans lifting leg weights, a resistance exercise. In contrast, JNK generally was not activated in muscle when the volunteers performed cycling, an endurance exercise.

But a significant minority of test subjects did show some JNK activation in their leg muscles during endurance exercise. That activation might prevent endurance adaptations, and it might explain why some people don’t respond as well to endurance exercise.

The Joslin team is looking at various ways to inhibit JNK activation. Among them, the scientists think that the activation of JNK during exercise depends on the amount of mechanical stress on the muscle, and that some people experience a higher level of mechanical stress during aerobic exercise. If so, developing approaches to reduce this stress might improve response.

Additionally, the researchers are doing experiments with animal models to try to treat this condition with drugs that inhibit JNK or related molecular targets.

The Joslin study has direct implications for the prevention of type 2 diabetes, the reduction of diabetes complications, and the prevention of cardiovascular disease. It could also prove useful for developing therapeutic approaches for building muscle to fight muscle-wasting diseases. (It also may help explain the “interference phenomenon” experienced by athletes during concurrent training.)

“We’ve begun to figure out how muscle decides whether it will grow or adapt for endurance, which really hasn’t been known,” Lessard sums up. “And we’re finding that this process is directly linked to the risk of type 2 diabetes.”

Lessard and her colleagues are now testing this hypothesis in a study analyzing the JNK biological pathway during endurance exercise, comparing people at heightened risk of type 2 diabetes versus people of normal risk.

If over-activation of the JNK pathway during endurance exercise does indeed boost the risk of diabetes, and if scientists can figure out a way to stop that process, “we might be able to reverse the risk in some people,” Lessard speculates.

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Story Source:

Materials provided by Joslin Diabetes Center. Note: Content may be edited for style and length.

https://bit.ly/2Khh6Vj

Apricus Plans Merger with Seelos to Advance Late-Stage CNS Pipeline

Apricus Biosciences, Inc. (Nasdaq: APRI) announced the signing of a definitive agreement to merge with Seelos Therapeutics, Inc., a privately-held biotechnology company, in an all-stock transaction.

The merged company will focus on the development and commercialization of central nervous system (CNS) therapeutics with known mechanisms of action in areas with a highly unmet medical need. Upon completion of the proposed merger, the name of the merged company will be Seelos Therapeutics, Inc., and the company is expected to begin trading on the Nasdaq Capital Market under the ticker symbol ‘SEEL.’ Seelos will maintain its headquarters in New York, New York.

‘Following a comprehensive review of strategic alternatives conducted through a structured process, the Apricus Board of Directors has concluded that the proposed merger with Seelos is in the best interest of our shareholders, as it will provide an opportunity to create value from a diversified pipeline of late-stage clinical assets in areas of high unmet need,’ said Richard Pascoe, Chief Executive Officer (CEO) of Apricus. ‘Moreover, we believe that the Seelos management, led by Dr. Raj Mehra, is well positioned to advance Seelos’ robust pipeline towards regulatory approval and commercialization in the United States.’

‘The announcement of this merger with Apricus marks the beginning of the next stage of growth for Seelos,’ said Raj Mehra, Ph.D., CEO of Seelos. ‘We have built a strong foundation with a team of established industry leaders and a robust pipeline of transformative product candidates with proven mechanisms of action, including several late-stage assets. The transaction builds upon our shared vision to develop, advance and commercialize innovative therapeutics for patients with CNS disorders. We look forward to establishing a leadership position in the field of neurologic disorders, growing our team, driving long-term shareholder value, and bringing to market therapies for patients who currently have no viable treatment options.’

Seelos’ Pipeline

With a broad product pipeline, Seelos is well-positioned to address unmet needs in multiple CNS disorders. The Company is advancing late-stage therapeutic candidates with proven mechanisms of action, including:

SLS-002: intranasal racemic ketamine for patients with suicidality in post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). The clinical development program for SLS-002 includes two parallel healthy volunteer studies, expected to be followed by pivotal registration studies after an end-of-phase II meeting with the U.S. Food and Drug Administration (FDA). SLS-002 has shown promising efficacy in suicidality (with depression) with an unremarkable safety profile. Ketamine’s rapid antidepressant action is independent of NMDAR inhibition and involves early and sustained activation of AMPAR activation. With no other drugs currently approved in this indication, SLS-002 has the potential to address approximately 600,000 cases of suicidality in U.S. emergency rooms alone each year.

SLS-006: first-in-class, small molecule, partial dopamine agonist for Parkinson’s disease that has successfully completed phase II studies. Seelos intends to meet with the FDA and the European Medicines Authority (EMA) to discuss the plans for pivotal registration studies to commence in 2019. SLS-006 has shown remarkable efficacy in early-stage Parkinson’s disease patients as a monotherapy and as a potential adjunctive therapy in late-stage Parkinson’s disease patients upon co-administration with a low dosage of L-Dopa.

SLS-008: once-daily, oral CRTH2 (Chemo-attractant Receptor-homologous molecule expressed on TH2 cells) that focuses on an undisclosed pediatric orphan indication. Seelos has a ‘family’ of compounds under its SLS-008 program. Seelos intends to file an Investigational New Drug (IND) Application in this pediatric orphan indication with a highly unmet need for an effective oral therapy.

In 2016, Seelos established a multi-program partnership with Ligand Pharmaceuticals, Incorporated (Nasdaq: LGND) forming the basis for Seelos’ lead programs. Ligand has an established track record of licensing foundational assets at the early stages of company formation. The license agreement grants Seelos worldwide rights to develop and commercialize the SLS-006, -008, -010 and -012 programs from Ligand. Ligand is expected to be a shareholder of Seelos at the closing of the merger by way of an equity milestone payment from Seelos and is entitled to other potential future milestones and royalties for licensed programs.

About the Proposed Merger

Under the terms of the merger agreement, the holders of Seelos’ outstanding capital stock immediately prior to the merger will receive shares of common stock of Apricusupon closing of the merger. On a pro forma and fully-diluted basis, Seelos shareholders are expected to own approximately 86% of the merged company and current Apricusshareholders are expected to own approximately 14% of the merged company, subject to customary adjustments of net cash upon closing.

https://bit.ly/2Kje0zX

Progenics gets FDA OK for neuroendocrine cancer med

Progenics Pharmaceuticals, Inc. (Nasdaq: PGNX) today announced that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for AZEDRA (iobenguane I 131) 555 MBq/mL injection for intravenous use.

AZEDRA, a radiotherapeutic, is indicated for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy. AZEDRA is the first and only approved therapy for this indication.

AZEDRA can cause serious side effects including risk from radiation exposure, bone marrow problems and other cancers (myelosuppression and secondary malignancies), thyroid problems (hypothyroidism), elevations in blood pressure, kidney problems (renal toxicity), respiratory problems (pneumonitis), pregnancy warning (embryo-fetal toxicity), and fertility problems.

Pheochromocytoma and paraganglioma are neuroendocrine cancers that arise from cells in and around the adrenal glands. Pheochromocytoma and paraganglioma tumors frequently secrete high levels of hormones that can lead to life-threatening high blood pressure, heart failure, and stroke in these patients. Metastatic pheochromocytoma and paraganglioma may result in unresectable disease with a poor prognosis, including a five-year survival rate as low as 12%1. Before AZEDRA’s approval, there were no FDA-approved anti-tumor therapeutics for these cancers.

‘AZEDRA is a true breakthrough in treating pheochromocytoma and paraganglioma delivering an effective anticancer therapy to these tumors,’ said Dr. Daniel Pryma, Associate Professor of Radiology & Radiation Oncology and Chief, Division of Nuclear Medicine & Clinical Molecular Imaging at the Perelman School of Medicine at the University of Pennsylvania, the trial’s lead investigator. ‘With this innovative, rationally designed treatment, we finally have a therapeutic option that helps address patients’ needs.’

‘As the first FDA approved therapy for unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy, AZEDRA provides a new treatment option for physicians and their patients,’ said Mark Baker, Chief Executive Officer of Progenics. ‘AZEDRA has been shown to decrease the need for blood pressure medication and reduce tumor size in some patients. We are extremely grateful to the patients, their families and the investigators who participated in AZEDRA’s clinical development program. We also thank those who have contributed to the development of AZEDRA over many years.’

https://bit.ly/2LKirtg

Merck, Eisai Get FDA Breakthrough Tag for Endometrial Cancer Combo

Eisai Co., Ltd. and Merck & Co., Inc.Kenilworth, N.J., U.S.A. (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for LENVIMA (generic name: lenvatinib mesylate), the orally available kinase inhibitor discovered by Eisai, in combination with Merck & Co., Inc., Kenilworth, N.J., U.S.A.’s anti-PD-1 therapy KEYTRUDA (generic name: pembrolizumab) for the potential treatment of patients with advanced and/or metastatic non-microsatellite instability high (MSI-H)/proficient mismatch repair (pMMR) endometrial carcinoma (EC) who have progressed following at least one prior systemic therapy.

The LENVIMA/KEYTRUDA combination therapy is being jointly developed by Eisai and Merck & Co., Inc., Kenilworth, N.J., U.S.A. as part of the strategic collaboration announced in March 2018. This is the third Breakthrough Therapy designation for LENVIMA and the second Breakthrough Therapy designation for LENVIMA in combination with KEYTRUDA following the Breakthrough Therapy designation for the combination for advanced and/or metastatic renal cell carcinoma announced in January 2018.

The Breakthrough Therapy designation is an FDA program intended to expedite development and review of medicines for serious or life-threatening conditions. In order to qualify for this designation, preliminary clinical evidence must demonstrate that the drug may provide substantial improvement over currently available therapy on at least one clinically significant endpoint. The benefits of this Breakthrough Therapy designation include more intensive guidance on an efficient clinical development program, access to senior FDA managers and experienced FDA staff to help accelerate review time, as well as eligibility for rolling review and potentially priority review.

This Breakthrough Therapy designation was based on interim results of the EC cohort in Study 111/KEYNOTE-146, which were presented in June 2018 at the 54th American Society of Clinical Oncology (ASCO) Annual Meeting.1,2 Study 111/KEYNOTE-146 is a multi-center, open-label, single-arm Phase 1b/2 basket trial evaluating the efficacy and safety of LENVIMA in combination with KEYTRUDA in patients with selected solid tumors.

‘This second Breakthrough Therapy designation for the LENVIMA/KEYTRUDA combination represents another step forward in our collaboration with Eisai and supports the continued evaluation of this combination in more than 11 types of cancer,’ said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. ‘We will continue to work closely with Eisai to build on the robust data for the LENVIMA/KEYTRUDA combination in advanced endometrial carcinoma in an effort to offer a new option for these patients and potentially help address a critical unmet need.’

‘We designed Study 111 to learn as much as we could about the LENVIMA/KEYTRUDA combination as efficiently as possible, driven by a sense of urgency to bring forward a potential new treatment option for patients in need,’ said Dr. Takashi Owa, Vice President and Chief Medicine Creation Officer, Oncology Business Group, Eisai. ‘We are encouraged by the continued activity seen in patients with endometrial carcinoma, and the latest Breakthrough Therapy designation for LENVIMA and KEYTRUDA has strengthened our commitment, as part of our human health care mission, to expedite the path to ultimately benefitting patients living with endometrial carcinoma as quickly as possible.’

https://bit.ly/2AKCdQv

Abbott Expands Directional Deep Brain Stimulation for Parkinson’s, tremors

Parkinson’s disease and essential tremor patients can now benefit from upgraded functionality with Abbott’s Infinity™ DBS system. Abbott (NYSE: ABT) today announced U.S. Food and Drug Administration (FDA) approval for an over-the-air software upgrade for all currently implanted Infinity DBS systems that delivers magnetic resonance (MR)-conditional labeling and innovative features. This life-changing technology from Abbott helps patients with progressive diseases live better.

Prior to the latest Abbott approval, people new to deep brain stimulation (DBS) therapy or those living with older systems from other manufacturers may have experienced barriers in accessing the most advanced DBS therapy options because of the potential need for an MRI in the future. With its updated labeling, Abbott has addressed this challenge with the Infinity DBS system’s improved therapy platform — the first and only FDA-approved MR-conditional directional DBS system.

“With this software upgrade, Abbott delivers on a promise to develop powerful features that strengthen the Infinity DBS system’s already patient-centric platform, which uses familiar Apple technology and frees the patient from recharging their device,” said Binith Cheeran, M.D., medical director of movement disorders at Abbott. “We are committed to continued innovation in neuromodulation, developing ongoing advancements and efficiencies for physicians and, most importantly, helping thousands of people who are battling movement disorders live fuller lives.”

This new approval allows existing implanted Infinity DBS systems to be upgraded via secure Bluetooth^® wireless technology without the need for surgery, giving full-body MRI conditional labeling to the entire Infinity DBS system, along with the suite of system upgrades.

“Today’s announcement of the newly released MRI-compatibility of the Infinity DBS system reflects Abbott’s continued commitment to patient-centric, cutting-edge care — where the patient’s options are expanded by the therapy instead of limited by it,” said Brian Kopell, M.D., a neurosurgeon and director of the Center for Neuromodulation at Mount Sinai Health System in New York City.

Parkinson’s disease and essential tremor are neurologic conditions known as movement disorders, which are caused by a communication breakdown throughout the central nervous system. This can result in a debilitating loss of muscle control, involuntary movement and reduced coordination. At present there are no proven cures for movement disorders. Treatment options like Abbott’s DBS system focus on alleviating symptoms to improve quality of life.

Abbott’s Infinity™ DBS system with directional leads is designed to direct stimulation toward targeted areas of the brain to maximize patient outcomes and limit side effects. The platform’s future-ready technology is built with the ability to significantly upgrade the capabilities and new therapy features of the Infinity DBS system through simple, over-the-air updates.

Abbott’s Infinity DBS system is the world’s first and only DBS system operating on an iOS software platform with Bluetooth^® wireless technology. Clinicians can streamline the programming process with an iPad mini device using Abbott’s new Informity™ Programming Software to become more efficient in their practice and achieve optimal outcomes with directional leads. Patients can discreetly manage their symptoms with their Infinity DBS System iPod touch controller.

Data continues to show that patients gravitate toward medical devices that are intuitive and low maintenance, such as with the Infinity DBS system’s dual channel recharge-free device. Using an approach with patients at the center of their therapy experience, Abbott’s neuromodulation portfolio is driven by science, data and patient input to help people suffering from movement disorders feel as normal as possible.

“Our patients and our clinical team are seeing clear clinical benefits with Abbott’s directional lead DBS therapy,” said Craig van Horne, M.D., Ph.D., director of the Deep Brain Stimulator Center at the University of Kentucky’s Neuroscience Institute. “The combination of directional lead therapy, MRI capability and simplicity in optimized programming could lead to a new standard of care for DBS therapy.”

Abbott’s Infinity DBS system is also CE Mark approved and has been used in nearly 30 countries, most recently in Russia, Saudi Arabia and Taiwan. For U.S. important safety information, visit: https://abbo.tt/2JSxXBC.

https://bit.ly/2OC2FOM

Teva hit as sales forecast disappoints market

Teva Pharmaceutical Industries on Thursday raised its profit outlook for 2018 after reporting a smaller than expected drop in second-quarter net profit, but its shares tumbled eight percent on disappointment over its unchanged revenue outlook.

The world’s largest generic drugmaker also reaffirmed that the U.S. Food and Drug Administration is due to make a decision in the middle of September for its migraine treatment fremanezumab, which it had originally hoped to launch in June.

“We will be ready to launch immediately after,” CEO Kare Schultz told a conference call.

Teva’s drug will be priced similar to Amgen’s migraine treatment that was launched in May – which after discounts is close to $6,000 per patient a year, he told Reuters.

“We are confident we can get significant market share,” he said, noting Teva’s drug is taken every three months, rather than monthly for Amgen’s drug.

Heavily-indebted Teva has been counting on its migraine treatment to revive its fortunes, though its release has been delayed due to U.S. regulatory concerns about the manufacturing process.

In a bid to cut debts, Teva late last year said it would combine its generic and speciality medicine businesses, cut more than a quarter of its workforce and close or sell 10 of its factories.

Teva earned 78 cents per share, excluding one-time items in the April-June period, down from $1.02 a year earlier.

Revenue fell 18 percent to $4.7 billion (£3.6 billion) due to continued price erosion in the company’s U.S. generics business, generic competition to its multiple sclerosis drug Copaxone and loss of revenue following the divestment of certain products and discontinuation of some activities.

Copaxone revenue in North America in the second quarter decreased by 46 percent to $464 million. In Europe, Copaxone sales edged up 1 percent to $140 million.

SHARES SLIDE

Analysts had forecast Teva would earn 64 cents a share ex-items on revenue of $4.74 billion, according to Thomson Reuters I/B/E/S.

For the full year, Teva raised its forecast for adjusted EPS to $2.55-$2.80 from $2.40-$2.65 estimated last quarter. It maintained its outlook for revenue of $18.5-$19 billion.

Analysts were forecasting EPS of $2.69 on revenue of $18.99 billion.

“Relative to expectations that is going to disappoint,” RBC Capital Markets analyst Randall Stanicky said.

“Perhaps what is more concerning is the light revenue with virtually all U.S. segments down year-over-year, which to us will raise questions around what impact the aggressive cost cuts are having on the business which is our primary concern for the medium to long term outlook.”

Teva’s shares were down 8 percent on the Nasdaq by 1440 GMT.

It said it had cut 8,300 jobs so far as part of plans to cut 14,000 announced last year.

“The restructuring program is on schedule, we have already achieved a significant cost base reduction towards our target for the year and we continue to reduce our net debt,” Schultz said.

Teva said its net debt has fallen to $28.4 billion, down from a peak of $35 billion, which resulted from its purchase of Allergan’s generic drug business Actavis for $40.5 billion in 2016. Schultz said Teva’s filing for a generic version of Mylan’s EpiPen was being reviewed by the FDA.

“We are hoping sometime in the coming months to have a clarification, hopefully a positive clarification, so that we will be able to launch a generic EpiPen in the U.S.,” he said.

https://bit.ly/2ABw9tk