This commodity is about how a anamnesis agenda abortion acquired a anniversary of photographs to disappear, what I did to try to balance them via software, again concrete abstracts services, and the admired acquaint to be abstruse about anamnesis cards, bifold agenda slots, and backups to anticipate such a daydream book from happening.
Landscape expeditions can be demanding in the continued canicule of summer, alike added so if you are additionally accomplishing night photography. Afterwards aerial to Seattle, I accustomed at the bank of Olympic Civic Park about 11 PM – abounding appearance Treasured Lands as a acme of my assignment in the civic parks, but I am far from actuality done with them! Seeking stars, I woke up afore 2 AM for the abbreviate window amid moonset and ample twilight. However, the abyssal band had formed in while I was hiking to the beach, and I burst until accomplished aurora time afterwards alike seeing a sliver of sky. The aing day, aback I had to drive from Heart of the Hills Campground and backpack 45 annual to Hurricane Hill, I rose afore 1 AM.
Note that the computer sees 8.2 GB, but it was a 64 GB card. Lexar abutment appropriate several added apps, including Ontrack EasyRecovery which has a "technician" adaptation with a $500/year licensing cost. As those apps accommodate a balloon access that allows you to attack to ascertain files, and crave you to pay the fee abandoned to absolutely balance them, I took anniversary of them for a circuit afterwards success. There are a lot of accretion programs around, but if the absurdity is accouterments rather than software, you can try all the programs in the world, and they won't do you any good.
Would you accept proceeded with the accretion at this price?
Although you don't about apprehend it in reviews, my capital complaint with the Sony a7R II camera is sensor dust consistent from the mirrorless architecture and an abortive sensor dust charwoman arrangement – it mechanically all-overs the sensor application the angel stabilization actuators. To cope, I assignment with two camera bodies in adjustment to abbreviate lens changes. The accomplished 24-105 FE stays on the primary camera which is acclimated for best of the photographs, while I adeptness for the accessory camera aback I charge added specialized lenses. On that trip, I had bootless to do drive backups and the damaged anamnesis agenda was in the primary camera, which meant that it absolute the majority of a week's annual of work, and allegedly the best photographs. However, I retained accessible images from the additional camera, a few of which allegorize this post.
I absitively adjoin proceeding with the attempted recovery, extenuative me the abeyant disappointment of abortion or costs. It is not that the pictures aren't annual the bulk asked. Rather, including all expenses, the cruise bulk me abandoned a atom of that amount. This algebraic didn't annual for my time, but no amount how backbreaking the accomplishment felt, that time was spent on a action that I abundantly enjoy. Losing the pictures did not rob me of the adventures I had nor of the aloof I did, and rather than attractive aback by advance in the recovery, I chose to attending advanced by extenuative the money for a echo cruise – and a new camera.
The beyond cessation actuality is that attempts to apprehend a agenda with accretion software may not consistently work, concrete accretion casework are expensive, and additionally not affirmed to work. Alike afterwards three decades in photography, the adventure able several acquaint for me.
The adversity drew home the point that anamnesis cards do abort catastrophically. Both abstracts companies begin austere concrete damage, but that was a agenda that had been acclimated for a year afterwards any distinct glitch, so neither "dead on arrival" nor accomplished any reasonable activity assumption – which by the way nowadays is best than abstruse obsolescence. It had never been subjected to any anatomy of corruption afore as it spent best of its activity in the camera, and above-mentioned to abortion went beeline from the camera to a agenda reader. There were absolutely no warnings nor reasonable explanations.I accept been application agenda cameras aback the aboriginal canicule of full-frame in the aboriginal 2000s (remember the $8,000 Canon 1Ds series?) afterwards any agenda failure, while during that time, I accept had to alter a half-dozen bootless adamantine drives. This fabricated me brash in beam technology.
If you browse the internet, you will see that I was far from actuality alone. Absolutely a few added able photographers (some with array of branch clients) accompaniment that they accept never accomplished any agenda abortion and that aback it happened, they were consistently able to accomplishment images with accretion software. Clearly, my acquaintance has been different. The actuality that you've been advantageous doesn't beggarly that your luck won't run out at some point, as it did for me – and others. As we will see next, a quick assay of chump reviews shows that anamnesis agenda abortion is not that rare.
The agenda that bootless is a Lexar Able 1000x 64GB SDXC UHS-II/U3, which is amid Lexar's top band of cards and accounted "professional" by the manufacturer. I acclimated to accept that any anamnesis agenda from a acclaimed cast would be reliable. If in addition, you bought it from a acclaimed vendor, affairs that you'd get a affected of ambiguous believability would additionally be low. Sandisk and Lexar are two of the best acclaimed brands, and I've acclimated alone their cards, depending on the best accord I could acquisition at the moment.
Because of that belief, I didn't pay abundant absorption to chump reviews, adopting the attitude that annihilation is 100% foolproof and afflicted association can accept a bad acquaintance with any product. Besides, a quick glance at the ratings appearance that about all cards are rated amid 4-stars and 4.5-stars, so they charge be acceptable products, right?
I actually had aloof advised the pics on my Nikon D610 camera and amid the agenda into my agenda clairvoyant and got a bulletin that it was not formatted (which it was – I architecture every agenda aback it's new). I put the agenda aback into my camera – and aforementioned Architecture error.
If we accept that 1-star reviews are absolutely the blazon you'd leave if the agenda absolutely failed, from that baby sample, we can see that some cards are four times added acceptable to abort than others. This abstracts additionally suggests that there is a botheration with those UHS-II Lexar cards. On the added hand, the Lexar UHS-I agenda that I accept acclimated for several years gets a assuredly low 3% of 1-star reviews.
The assignment actuality is that not all cards are equal, alike amidst those from a top brand. And if they can accept such a aerial abortion rate, anticipate about cards from beneath acclaimed or affected brands! By the way, attractive at those numbers additionally announce that abortion bulk with SD cards is far college than CF cards.
Some abrogating chump reviews are barmy because they are abiding in user error, or because they affair themselves with commitment rather than the product's affection or performance. However, abrogating reviews are about added cogent than absolute reviews.
If you anticipate that one shouldn't focus on the abrogating while the all-inclusive majority of reviews are positive, accede that on Amazon, the boilerplate appraisement for a artefact is 4.4 (out of 5) as begin actuality by allegory 7 actor reviews. Alike a artefact with an boilerplate 4.0 appraisement (4-star) is beneath average. The ample majority of accessories are rated aloft 4.0, so the aberration amid a abundant artefact and a subpar artefact is beneath than 1 (star) on average. On the added hand, we've aloof apparent that the cardinal of 1-star reviews for altered cards varies by a agency of four.
If your camera has bifold anamnesis slots, the best accessible and foolproof way to anticipate abstracts accident from anamnesis agenda abortion is to set the camera to address to two cards accompanying so that it creates a aback up in absolute time. Now that anamnesis cards accept become actual affordable, you can buy two sets of cards with abundant accommodation to aftermost you for your accomplished cruise so you don't accept to reclaim any card, and you consistently accumulate two datasets.
Dual anamnesis agenda slots are accepted in high-end DSLRs cameras, and afterwards abbreviating them in their aboriginal two ancestors of mirrorless cameras, Sony has started accouterment them in the a9 and a7 III alternation (a acceptable archetype of alert to your customers, aback there were complaints about the single-slots in antecedent cameras), with the admonition that the additional aperture is UHS-I, so application accompanying autograph will abate the allowances of the faster UHS-II capital slot. I was cerebration of absence the a7R III bearing and delay for the assured a7R IV, but the adventure prompted me to upgrade.
Recently appear full-frame mirrorless cameras from Canon and Nikon accept been greeted with an disproportionate cardinal of Internet comments about their distinct anamnesis agenda slot. We saw abounding claims that no able would use cameras with a distinct anamnesis slot.
But the actuality is that some able photographers debris to use the additional aperture for aback up alike aback their camera has one, and for specific reasons. To alpha with, aback I was cutting the Canon 1Ds series, I did not set up the cameras to accompanying write, possibly because the admeasurement of the anamnesis cards accessible aback again fabricated it binding to accomplish circadian backups.
More recently, Lloyd Chambers uses his dual-slot Nikons as distinct aperture SD cameras because he is affronted by the camera behind to the amiss agenda — this reminds me of Ted Orland's adage "Owning added than one lens assures that you will consistently accept the amiss lens on the camera for any accustomed picture" — while Thom Hogan uses his bifold aperture Nikon as a distinct aperture XQD camera because the SD aperture slows bottomward the camera.
Colby Brown thinks that "there is no point in authoritative two copies of your SD cards" and appropriately sets his Sony a7R III to auto about-face as he estimates he has a college adventitious of missing a attempt because of a abounding agenda than an SD agenda abortion – what I acclimated to do with the 1Ds.
I admiration if those statements about the aberration of agenda failures do a disservice to beneath accomplished association because what isn't acutely appear is that, although those photographers allegedly don't abhorrence agenda failure, they additionally accept all-encompassing advancement strategies application adamantine drives.
If there is one affair that I ambition others apprentice from my misfortune, it is that a solid advancement plan is necessary. There are absolutely a few means to go about it.
Several brands now action ruggedized carriageable drives. SSDs, which accept collapsed in price, are abundant beneath decumbent to accident than HDDs. Application drives for backups, you can do a circadian (or alike added frequent) backup, and accept added than two copies of your data.
On the added hand, compared to the in-camera bifold slots backups, drive backups are not in real-time, so you could possibly lose a day of data. Added importantly, you charge to bethink and booty the time to accomplish the backups – aback maybe you'd aloof rather go to sleep. During that blighted trip, I agitated a carriageable drive (the HyperDrive ColorSpace UDMA3) yet due to a aggregate of fatigue, loaded agenda and complacency, I did not use it.
Another acumen was that my carriageable drive had accomplished a annihilate during the antecedent trip, banishment me to skip backups, which in about-face bankrupt my addiction of authoritative them regularly. This brings up the point that with drive-based backups, you accept to backpack added gear, which could additionally fail. Alike if you backpack several USB alien drives, you still depend on your laptop for your adeptness to accomplish drive backups.
With in-camera dual-slot backups, accustomed the availability of huge accommodation cards, you could shoot best trips on a distinct brace of cards, but if commodity adverse happened to your camera, you'd lose everything. Alternatively, you could use abate cards, and already a brace of cards is filled-up (or accession beginning in accommodation or time is reached), anniversary of them can be stored at an absolute area to abbreviate the accident of accident due to theft. While the additional access increases the affairs of a botheration because you accept added cards to manage, it minimizes the adverse furnishings of problems.
For now, I accept acclimatized on an access which I anticipate provides me the best back-up with the atomic effort: use the additional aperture of the a7R III for real-time advancement with a medium-sized card, additional do a circadian advancement on a distinct independent carriageable adamantine drive. I about adopt them to laptops because they are appreciably abate and abundant faster to arrange for backup.
Eventually, my abstracts accident was acquired by my own neglect. This is aloof my experience, but I achievement it's been advantageous to you to apprehend about it.
About the author: QT Luong is accepted for actuality the aboriginal to photograph all America's 60 Civic Parks — in ample format. Ken Burns and Dayton Duncan featured him in The Civic Parks: America's Best Idea. His photographs are abundantly appear and accept been the accountable of large-format books including Treasured Lands (winner of 6 civic book awards), abounding bi-weekly and annual affection articles, abandoned arcade and building exhibits beyond the U.S. You can acquisition added of his assignment on his website, Twitter, Instagram, and Facebook. This commodity was additionally appear here.


On booking your details will be sent out to you by regular post together with your receipt.
VIA THE BACK GATE OF THE GALLERY.
Alley-way off Wilton Road next to the Park.
All payments taken at the session.
Easy-bite lessons that can give a jump start to a creative path.
See 'Access' as above - via the back gate.
Payments taken at the Session.
Contact Francesca before attending, so she can guide you about availability of a place.
Professional Artists and Trained Tutors.
Introduction to creating small pieces, learning techniques of fusing and creating colour from a variety of inclusions: metals, oxides etc. You will go home with a variety of small designs which can then be made into small window hangings/pictures, or jewellery, or for greetings cards.
Creating at least one style of Landscape using handmade and waste papers. A day of experimenting ..... You will go home with at least one finished picture. This will suit anyone new to craftwork, as well as those with more experience who wish to enjoy a day creating an original piece of artwork.
This will interest those who love the different possibilities of paper, cutting, and arranging patterns inspired by imagined or traditional patchwork designs...... You will go home with one finished piece.No experience of quilting or craft work is needed.
A one-day course to learn the traditional techniques of this amazing upcycling craft. You will make a small sample piece which will prepare you for making larger rugs, for floor covering or as wall hanging - as a feature piece for a cushion. Everything is provided that you need to get going, and advice will be given as to what designs can work, and what is involved.
We welcome you to join these Creative Courses.
Festival Activities in the Shed and Cabin studio spaces, and Sculpture Garden to the rear of the main Gallery.


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Saudi Arabia, France discuss peaceful atomic energy cooperation
RIYADH(RAHNUMA): Saudi Arabia's Minister of Energy Prince Abdulaziz bin Salman held a meeting on Saturday with French Minister of Economy,…
Study on Saudi workplace wellness identifies key challenges, suggests solutions
DDUBAI(RAHNUMA): Although mental health issues present a significant challenge to productivity, a benchmark survey in Saudi Arabia has revealed yawning gaps…
Saudi Cabinet reviews political and economic efforts to boost cooperation
RIYADH(RAHNUMA): The Saudi Cabinet on Tuesday reviewed a number of political and economic decisions and initiatives designed to strengthen international…
Saudi Arabia leads Arab condemnation of tearing up of Qur'an in The Hague
RIYADH(RAHNUMA): Saudi Arabia has led Arab states' condemnation on Tuesday of tearing apart a copy of the Qur'an in The…
Saudi Aramco talks sustainable development at Real Estate Future Forum in Riyadh
RIYADH(RAHNUMA): Saudi Aramco highlighted its experience with sustainable development during the second edition of the Real Estate Future Forum in…
Saudi Design Festival 'tailor-made' for industry growth, says director
RIYADH(RAHNUMA): The Saudi Design Festival is "tailor-made" to promote sustainable growth in the industry, the event's director and co-founder, and…
Saudi foreign minister, Interpol chief discuss combating crime, terrorism
DAVOS: Saudi Arabia's Foreign Minister Prince Faisal bin Farhan met with the Secretary-General of the International Criminal Police Organization (Interpol)…
Saudi foreign minister meets Tunisia's prime minister at WEF 2023 in Davos
RIYADH(RAHNUMA): Saudi Foreign Minister Prince Faisal bin Farhan met with Tunisia's Prime Minister Najla Bouden on the sidelines of the…
Saudi deputy foreign minister receives EU, India envoys
RIYADH(RAHNUMA): Saudi Deputy Foreign Minister Waleed bin Abdulkarim Al-Khuraiji met Sven Koopmans, EU special representative for the Middle East peace…
Saudi climate affairs envoy meets Norwegian environment minister at WEF 2023
RIYADH(RAHNUMA): Adel Al-Jubeir, the Saudi minister of state for foreign affairs and the Kingdom's climate affairs envoy, and Espen Barth…

redpajama_set_name: RedPajamaCommonCrawl


I completed a BSc and MSc in Mathematics and a PhD in Mathematics Education at the University of Warwick. I then spent four years as an assistant professor with a joint appointment in Mathematics and the Graduate School of Education at the Rutgers University in the USA. I returned to the UK in 2005, and worked as a teaching fellow at Essex University before taking up my current post at Loughborough in 2007.
In addition to publishing research in undergraduate mathematics education, I have now written two research-based study guides for mathematics students and a popular mathematics book Mathematics Rebooted. For links to papers and sample chapters from the books, see my personal website.
Proof comprehension and mathematical reading.
Use of examples in mathematical reasoning, including use of diagrams.
Understanding in topics such as real analysis.
Book Reviews Editor for the International Journal of Research in Undergraduate Mathematics Education.
Awarded the 2012 Selden Prize for Research in Undergraduate Mathematics Education.
Author of the research-based study guides How to Study for a Mathematics Degree and How to Think about Analysis.
Awarded the National Teaching Fellowship in 2015.


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About Our OrganizationSuccess Stories
Michael's Story
Meet Michael I always remember feeling unwanted and unloved.
As a child born to a woman in her 40s, Michael never felt cared for. "At 14, I began taking hallucinating drugs." When he was 18, he was arrested for possession of LSD. He spent time in jail where he felt a spiritual awakening. He was sent to a shock camp and then was sentenced to two years of probation.
"A hell on my soul was unleashed."
Once out of incarceration, Michael started smoking marijuana and drinking beer. By the time his probationary period ended, he was back to using his drug of choice, heroin. The result was a steady decline that lasted years, and Michael finally became homeless. A blood clot/staph infection landed him in the hospital, where he also had surgery. He then began a long journey to get out of the hell in which he had been living.
Michael and Geri, his case manager at CFC
"Michael was here because he wanted to get well."
After time in an inpatient addiction treatment center, Michael entered the ReStart outpatient program sponsored by Family and Community Services. As his time in the program progressed, he became impressed with the commitment of some of his peers. "I enjoyed the processing and relationship-building that happened in this group," Michael said. ReStart Counselor Geri Gigliotti witnessed Michael's own commitment to recovery. "I remember Michael saying he was looking for a miracle…He just surrendered…and that was the beginning of his turnaround."
"Before I took my will back, my will was in charge of my life."
Michael says he now lives in God's will, and he has "a desire to do the right thing of service to a higher power and to others." He acts as a mentor to others in Alcoholics Anonymous, and finds their journeys inspire him. Michael now wants to go to school for either pastoral care or social work, and he hopes to improve his relationship with his family. "There are no shortcuts or casual options on this road to living clean and serving our higher purpose." Learn more about Restart.


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Sep 9 Prozac and other antidepressants may be causing antibiotic resistance
Originally published on Science Codex
A key ingredient in common antidepressants such as Prozac could be causing antibiotic resistance according to new University of Queensland research. A study led by Dr Jianhua Guo from UQ's Advanced Water Management Centre focused on fluoxetine, a prescription drug used to help people recover from depression, obsessive-compulsive disorder or eating disorders. Dr Guo said while overuse and misuse of antibiotics is generally considered the major factor contributing to the creation of 'superbugs', researchers were often unaware that non-antibiotic pharmaceuticals could also cause antibiotic resistance.
"Our previous study reported that triclosan, a common ingredient in toothpaste and hand wash can directly induce antibiotic resistance," he said. "We also wondered whether other non-antibiotic pharmaceuticals such as fluoxetine can directly induce antibiotic resistance."
Up to 11 per cent of the fluoxetine dose a patient takes remains unchanged and makes its way through to the sewer systems via urine.
"Fluoxetine is a very persistent and well-documented drug in the wider environment, where strong environmental levels can induce multi-drug resistance," said Dr Guo. "This discovery provides strong evidence that fluoxetine directly causes multi-antibiotic resistance via genetic mutation."
Fellow researcher Dr Min Jin said that under laboratory conditions, the higher the exposure concentration was, the faster the mutation frequency increased with time. "It has previously been an invisible factor in the spread of antibiotic resistance, but we should consider this a warning. Further work is required to investigate effects of fluoxetine on antibiotic resistome in human gut microbiota."
Antimicrobial resistance has become a major threat to public health globally with approximately 700,000 people a year dying from antimicrobial-resistant infections.
This is predicted to reach 10 million people by 2050 unless global action is taken now.
Sep 10 Diversity in our genes may hold the key to the spread of infections
Sep 9 'Knowing your enemy' best advice in tackling infectious diseases
Aug 19 Wasted antibiotics causing resistance
Dec 11 Alzheimer's drug may help battle antibiotic resistance
Jan 22 Research may offset antibiotic resistance


Noel Acciari had to wait a year to play his first game at Providence College, but he wasted no time in making an impact when he finally got on the ice last Friday night.
Acciari - who was ruled ineligible last season by the NCAA Clearinghouse - recorded his first point just 3:15 into the game, setting up a goal by Mark Jankowski.
"Unbelievable feeling just to get out there again,'' the former Hendricken All-Stater from Johnston said after practice on Monday.
Acciari, is listed at 5-foot-11, 195 pounds, but plays bigger. He credits PC strength and conditioning coach Ken White, with whom he worked last winter and over the summer.
"Coach White worked me real hard, and encouraged me to get ready for this year,'' said Acciari, who centered his former Kent School roommate Drew Brown and Kevin Rooney on Friday against Sacred Heart and Brandon Tanev and Chris Rooney on Saturday against Boston University.
Coach Nate Leaman was impressed by Acciari on both nights.
"He was excellent. He's one of our strongest players. He's picked up on everything really quick. He can hit like a truck. He's one of the hardest-hitting kids I've ever coached.


Russell, Sarah L (2011) A Randomised Clinical Trial Investigating The Most Appropriate Conservative Management Of A Frozen Shoulder. Masters thesis, University of Central Lancashire.
'Frozen Shoulder' is a term which describes a combination of shoulder pain and stiffness that causes sleep disturbance and marked disability, and which runs a prolonged course (Hanchard et al 2011). Physiotherapy has been advocated; however there is no robust evidence on the superiority of any one treatment modality (Callinan et al 2003).
The aim of this study was to evaluate the effect of an exercise class compared to multimodal physiotherapy and a home exercise programme in patients with frozen shoulder. The objectives were to identify that clinical scores were effective at detecting change in the different treatment groups and to provide recommendations for the physiotherapeutic management of frozen shoulder. The study design was a randomised controlled trial with seventy five patients enrolled. The primary outcome measure was the Constant score, secondary outcome measures included the Oxford Shoulder Score (OSS), Hospital Anxiety and Depression Scale (HADS) and the short form 36 item health survey (SF-36). A repeated measures one- way analysis of variance on the outcome data was conducted.
Results from the Constant score and OSS indicate that at six weeks, six months and one year, an Exercise Class was more effective than Multimodal Physiotherapy or Home Exercises. The results from the HADS indicate that the Exercise Class was more effective than Multimodal Physiotherapy or Home Exercises at six weeks and six months. However, at one year Multimodal Physiotherapy was more effective than the Exercise Class and Home Exercises.
This study provides an original contribution to knowledge in frozen shoulder and has important implications for enhancing clinical practice. The findings suggest that a hospital based exercise class produced a rapid recovery with a minimum number of visits to the hospital. Physiotherapy could also be considered to optimise speed of recovery of frozen shoulder. The Constant score, OSS and HADS are recommended in the management of frozen shoulder. Finally, GPs and physiotherapists require training in the clinical diagnostic accuracy of frozen shoulder. The need for further research in this area is emphasized.


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Overview of the pre-clinical and clinical studies about the use of CAR-T cell therapy of cancer combined with oncolytic viruses
Ali Zarezadeh Mehrabadi2,
Fatemeh Roozbahani3,
Reza Ranjbar4,
Mahdieh Farzanehpour1,
Alireza Shahriary5,
Ruhollah Dorostkar1 &
Hadi Esmaeili Gouvarchin Ghaleh ORCID: orcid.org/0000-0001-8562-22951
World Journal of Surgical Oncology volume 20, Article number: 16 (2022) Cite this article
Cancer is one of the critical issues of the global health system with a high mortality rate even with the available therapies, so using novel therapeutic approaches to reduce the mortality rate and increase the quality of life is sensed more than ever.
CAR-T cell therapy and oncolytic viruses are innovative cancer therapeutic approaches with fewer complications than common treatments such as chemotherapy and radiotherapy and significantly improve the quality of life. Oncolytic viruses can selectively proliferate in the cancer cells and destroy them. The specificity of oncolytic viruses potentially maintains the normal cells and tissues intact. T-cells are genetically manipulated and armed against the specific antigens of the tumor cells in CAR-T cell therapy. Eventually, they are returned to the body and act against the tumor cells. Nowadays, virology and oncology researchers intend to improve the efficacy of immunotherapy by utilizing CAR-T cells in combination with oncolytic viruses.
Using CAR-T cells along with oncolytic viruses can enhance the efficacy of CAR-T cell therapy in destroying the solid tumors, increasing the permeability of the tumor cells for T-cells, reducing the disturbing effects of the immune system, and increasing the success chance in the treatment of this hazardous disease.
In recent years, significant progress has been achieved in using oncolytic viruses alone and in combination with other therapeutic approaches such as CAR-T cell therapy in pre-clinical and clinical investigations. This principle necessitates a deeper consideration of these treatment strategies. This review intends to curtly investigate each of these therapeutic methods, lonely and in combination form. We will also point to the pre-clinical and clinical studies about the use of CAR-T cell therapy combined with oncolytic viruses.
Cancer is a lethal disease discriminated by long-term inflammation [1]. Cancer impacted almost 19 million patients in 2020, and 10 million people died due to it. Thus, developing a stable infrastructure for preventing and caring activities is indispensable for this world health issue [2].
Cancer treatment involves a wide range of modalities, including chemotherapy, radiotherapy, surgery, and medications such as monoclonal antibodies [3]. Additionally, physicians and researchers in this field are now looking for new approaches with higher efficacy, specificity, and fewer complications. Adoptive cell transfer (ACT) and oncolytic viruses are two novel therapeutic methods; several clinical trials are being conducted regarding these modalities.
Engineered T-cells expressing chimeric antigen receptors (CARs) specific to cancer cells have recently attracted much attention. CARs are recombinant receptors typically targeting surface molecules (here, cancer cell surface molecules) [4]. Generally, CARs include three main components: an extracellular antigen recognition domain of the single-chain fragment variant (scFv) region, a transmembrane domain, and an intracellular CD3ζ domain [5]. Novel CAR constructs evolve by adding co-stimulatory domains or targeting domains [6]. Autologous CAR-T cells can attack cancer cells and destroy them specifically.
CAR-T cell therapy is more effective in treating hematologic malignancies than solid tumors. For example, using CAR-T cells expressing anti-CD19 antigens (PAN B cell marker) has successfully treated acute lymphoblastic B-cell cancer of the children, non-Hodgkin lymphoma, and chronic lymphocytic leukemia [7].
The concept of immunotherapy in cancer has attracted the attention of physicians for centuries; thus, the relationship between microbial infection and mediated spontaneous tumor inhibition has been frequently assessed and discussed [8]. In the seventeenth to nineteenth centuries, different types of immunotherapy have been widely used. Two critical instances are using septic bandages for ulcerative tumor treatment and leaving surgical wounds open deliberately to accelerate wound healing [9]. According to the medical records of William Cole, the surgeon, he has treated cancer patients with bacterial lysates [10]. Oncolytic viruses selectively attack cancer cells, infect and lyse them, though they do not infect healthy cells. The oncolytic viruses are either wild viruses or laboratory-modified wild viruses. By using biotechnological approaches, a new era of viral-based therapies has started to cause fewer complications for the patients [11, 12]. In addition to oncolytic activity, OVs are very effective in stimulating inflammation and immune response against themselves and the tumor cells. However, the outcome of the immune response is associated with some complexities; the OV-mediated anti-tumor immunity is eventually effective [10, 13]. Many OVs act like vaccines and lead to robust and specific TCD8 + -mediated anti-tumor reactions, which are frequently associated with the formation of significant memory cells [14, 15]. Conclusively, OVs may turn into an effective therapeutic modality in treating various types of tumors soon. In cancer treatment, gene therapy is defined as using genetic molecules to manipulate target cells and tissues to treat cancer patients [16]. Two types of gene therapy modalities have been proven effective in recent years, including using CAR-T cells and oncolytic viruses for tumor treatment. Oncolytic viruses are independently ineffective in the treatment of cancers, especially giant and metastatic tumors. Hence, oncolytic viruses can be used in combination with other treatments [17], including immune checkpoint blockers [18] and CAR-T cell therapy [19]. The combination of oncolytic viruses and CAR-T cells can be considered a new complementary strategy to overcome the limitations of using each of these therapies alone. This review aims to highlight the importance of CAR-T cells and oncolytic viruses as well as their use in monotherapy and combination therapy.
Overview of oncolytic viruses
Viruses are intracellular infectious particles that rely on the host cells for survival and proliferation; viral particles lead to pathogenesis and inflammation in the host cells [20]. Viruses are composed of three main parts: Genome is the innermost part of the viral particles (RNA or DNA) surrounded and protected by a protein coating called a capsid. The outermost part of the viral particles is the lipid coating or envelope, which facilitates viral binding to the host cells. Oncolytic viruses have no difference, though DNA oncolytic viruses are superior to other viruses due to their more giant genome, high stability of their polymerase enzyme, genome homogeneity, and high proliferative ability [21]. RNA viruses are suitable for tumors of the central nervous system due to their small size and ability to cross the blood–brain barrier [22].
Using viruses in cancer therapy dates back to the early nineteenth century as the reported treatment of patients with leukemia following viral infections. In the 1950s and 1960s, our viral knowledge expanded acknowledgments to the significant advancements of cell culture systems. Viral therapy attracted particular attention, and many viruses such as hepatitis, West Nile, and Epstein-Barr virus were frequently used in cancer treatment. These studies provided valuable information despite the variable and controversial results [23,24,25]. Some of these studies provided promising results. For example, in 1956, 30 female patients with advanced epidermoid cancer of the cervix were treated with adenovirus. In most patients, tumor region necrosis was observed, which was limited to the cancer tissue leading to no damage to the healthy tissue [26]. In the 1970s and 1980s, using viruses as a cancer therapeutic method was neglected; two decades later, this therapeutic method re-emerged under the title of "oncolytic viruses" [24].
In recent years, virotherapy for cancer has remarkably progressed. Moreover, these viruses may be used for cancer treatment due to their unique characteristics. Talimogenge lahreparepvec [T-vec] was the first oncolytic virus identified and registered for treating irrecoverable metastatic melanoma in the USA in 2015 [27, 28]. This virus infected and hit tumor cells, stimulated macrophages, and dendritic cells with pattern recognition receptors (PRP) through pathogen-associated molecular patterns [PAMP] released from killed tumor cells [20, 29]. On the other hand, oncolytic viruses lead to DAMP production and activation of dendritic cells through tumor tissue destruction [30], and eventually, mature dendritic cells activate anti-tumor T cells by presenting tumor epitopes [31].
Some strategies such as using tumor-specific promotor and modification of viral protein may improve the oncolytic efficiency of the viruses, allowing the viral particles to merely infect tumor tissue without affecting healthy tissue [32]; moreover, antibodies, cytokines, and immune stimulants could be associated with the viral particles so that viral particles tolerate the tumor microenvironment and improve the efficacy [33].
Some oncolytic viruses, including parvoviruses, reoviruses, Newcastle disease virus, myxoma virus, Seneca Valley virus, and coxsackievirus, naturally have the ability of target cell recognition [34, 35]. These viruses proliferate after inserting the cells and releasing tumor-specific antigens, danger signals, interferon I production, and eventually tumor lysis and destruction [30]. They selectively enter their target cells (tumors) and do not infect healthy cells, though they induce immunity to other cells. On the other hand, some viruses, including adenovirus, herpes simplex virus, rubella virus, poliovirus, and vesicular stomatitis virus, do not inherit this feature and require genetic modification [34] (Table 1).
Table 1 A summary of the oncolytic viruses and their characteristics
In 1999, immune response induction by oncolytic cells was recognized via oHSV for the first time. This virus acted as an "in situ cancer vaccine" and induced tumor-specific CTL and tumor cell death by the effector T cells against inoculated tumors [15].
Like gene therapy, desired genes for proper intracellular function may be added to oncolytic viruses to substitute viral genes [36]. One of the fantastic ways that can be used to kill tumors is to induce a "suicide gene" in tumor cells [37]. It is noteworthy that desired tumor-associated antigens may bond to the oncolytic viruses' surface through electrostatic bindings, even without gene therapy or genetic engineering [38].
Overview of CAR-T and CAR-NK cell therapies
In the last years, genetically modified immune cells, mainly T cells and natural killer (NK) cells that express chimeric antigen receptors (CARs), have had significant success in killing cancer cells [39]. CARs expressed on T or NK cells can enable them to detect a specific antigen expressed on tumor cells in the patient. CARs include three main components: an extracellular domain for tumor antigen recognition, a transmembrane domain, and one or more intracellular signaling domains leading to T-cell activation. The single-chain fragment variable (scFv) of a CAR, typically consists of variable heavy (VH) and variable light (VL) chains of an antibody which are bonded by a linker peptide SCFV, binds to an intracellular signaling molecule composed of a CD3ζ signaling domain or an intracellular signaling immunoreceptor tyrosine-based activation motif (ITAM). On the other hand, co-activator molecules such as CD28 and 4-1BB may be involved in the intracellular domain of the CAR. The main advantage of CAR-based methods for cancer immunotherapy is that SCFV shows a considerably higher affinity for antigen binding compared with TCR. Moreover, unlike TCR, SCFV acts in an MHC-independent manner [40, 41].
CAR T or NK cell therapy process comprises several steps that can take several weeks. First, T or NK cells are isolated from the patient's or donor's blood through leukapheresis, and thereupon genetically modified ex vivo, using viral or non-viral transfection methods. The CAR-modified immune cells are then grown and multiplied in the laboratory until sufficient cell numbers are produced. When the CAR T or NK cells are prepared, the patient receives a brief lymphodepleting chemotherapy course, followed by CAR T or NK cell infusion [42].
More than 450 clinical trials analyze CAR-T cells to treat cancer, especially hematological malignancies [42]. Among these clinical trials, CD19-directed CAR T cells have shown remarkable anti-cancer activity in patients with B-cell malignancies. In total, the CAR-T cells have demonstrated fabulous clinical responses in the treatment of mostly relapsed or refractory hematological malignancies that led to four FDA-approved CAR T cell therapy including Kymriah, Yescarta, Tecartus, and Breyanzi over the past 4 years [42,43,44]. Despite the significant success in the treatment of malignancies, CAR T cell therapy has shown several challenges. First, treatment with CAR T cells can cause serious side effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [45]. Second, the autologous CAR T cell-manufacturing process can be long, costly, and laborious. Based on these limitations, other subsets of immune cells, such as natural killer (NK) cells, have received more attention in immunotherapy [46].
Up to now, 19 clinical trials involving CAR NK cells have been reported for the treatment of malignancies [42]. It seems that CAR NK cells can act as an alternative therapy option to CAR-T cells due to an intrinsic killing capacity of malignant cells and only a few adverse events related to insertional mutagenesis. CRS typically develops after CAR T cell administration due to elevated proinflammatory cytokines, such as IL-1, IL-6, and TNFα [47].
Notably, CAR NK cells are considered safe because they mainly secrete IFN-γ and GMCSF. In addition, the approved CAR T cell products have been autologous through the risk of graft-versus-host disease (GVHD) with the use of allogeneic T cells. Several clinical studies have shown that, unlike allogeneic T cells, allogeneic NK cells do not cause GVHD [48].
According to pre-clinical and clinical studies, CAR NK cell therapy is a considerable anti-cancer agent and is safer than CAR-T cell therapy [46]. Nonetheless, CAR-NK cell therapy encounters some limitations, such as the expansion and activation of primary NK cells in vitro, the hardness of storing and shipping NK cell products (due to the sensitivity of NK cells to cryopreservation), and the low transduction efficiency. Therefore, further research is still required to optimize CAR NK cell therapy [39, 42].
Combining oncolytic viruses with CAR T cell therapy
Chimeric antigen receptor (CAR) T cell therapy has generated significant excitement in managing hematological malignancies, but solid tumors pose various challenges. It seems that combinations of different targeted therapies may be required to attain efficient and complete responses in solid tumors [49]. Oncolytic viruses as potential anti-tumor agents can help CAR T cells simultaneously overcome some of the limitations found in solid tumors [21].
Generally, the anti-tumor function of tumor-targeting CD8 + T-cells depends on three signals, including TCR engagement, co-stimulation, and an inflammatory stimulus. The second-and third-generation CARs provide engineered T-cells with TCR engagement and co-stimulation signaling [50]. The inflammatory stimulation of CAR T cells is typically driven by cytokines like IL-12 or type I IFNs. Type I IFNs are essential natural mediators of antiviral and anti-tumor activity by stimulating host adaptive immunity. It is identified that OVs can induce an elevated type I IFN signature in the tumor microenvironment [51].
In addition, many solid tumors intervene with tumor-infiltrating immune cells by diminishing adhesion molecule expression on endothelium, decreasing chemokine production, and secreting extracellular matrix components to prevent T cells from reaching the tumor microenvironment [52]. As mentioned, impaired CAR T-cell trafficking into solid tumors is one of the main challenges faced in applying CAR T cell therapy. Previous studies has shown that an inflammatory tumor microenvironment with active dendritic cells promotes type I IFNs and IFN-γ secretion, and moreover co-stimulatory signals are essential for CAR T cell infiltration. Therefore, CAR T-cells are likely to benefit from the synergistic combination with OVs that enhanced CAR T cell migration into the tumor and persistence within the tumor microenvironment [51, 53].
The upregulation of programmed death ligand-1 (PD-L1) on cancer cells negatively regulates T cell function and contributes to cancer immune escape [54]. On the other hand, cancer cells also induce immunosuppressive signaling mediated by a variety of immune cells like Tregs, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), fibroblasts, and endothelial cells within the tumor microenvironment. These immunosuppressive phenotypes impede effector T-cell exclusion and function within the tumor microenvironment. Overcoming these mechanisms of immunosuppression can improve the efficacy of immunotherapy, especially CAR T cell therapy in solid tumors. It seems that the combination of OVs and CAR-T cells can negate the multiple immunosuppressive mechanisms and enhance the effector functions of T cells [52, 55].
OVs have recently been generated by genetic modification to have co-stimulatory molecules including OX40L, 4-1BBL, and GITRL to boost the local activation and expansion of effector T cells within the tumor microenvironment [51]. Moreover, OVs have been designed with additional transgenes encoding CD40 ligand (CD40L), increasing local CD40 activation within the tumor microenvironment. Owing to the expression of CD40 on a wide range of immune cells, including CD4+ T-cells, macrophages, and B-cells, activation of this pathway mediates anti-tumor immune responses [56].
Various pre-clinical research has evaluated different transgene-armed OV in combination with CAR-T cells [51]. The finding of these researches gave main insights into the anti-tumor impacts of CAR-T cells in combination with engineered-OVs (Fig. 1). Furthermore, the flexibility of the engineering process of OVs and CAR T cells can help researchers design the most appropriate combinations of recombinant OV and CAR T cell co-stimulation to the specific characteristics of the targeted tumor [57].
The anti-tumor impacts of CAR-T cells in combination with engineered-OVs.
In fact, the immune-stimulatory properties of OVs and the potential to arm OVs with therapeutic transgenes make them excellent partners to boost CAR T cells in vivo (Fig. 2). Nonetheless, the potential for combining OVs, CAR T-cell therapy, and an additional immunotherapeutic strategy are practically limitless [58]. Naturally, translation of pre-clinical experimental results to clinical trials cannot often be logical and acceptable because of using an immunodeficient mouse model (NOD SCID gamma mice), so this experimental system cannot model the interactions between OV and CAR T cells in the human immune system [59]. In addition, the double combination enhances concern about the safety of combining two potent proinflammatory immunotherapies. Finally, given that combining these two therapies is a new approach, many studies are needed to improve it.
Different levels of combined therapy of OVs with CAR-T cells. Oncolytic viruses exert their effects on cancer cells in a variety of ways. These viruses can lysis cancer cells to better activate APC cells, cause inflammation, and release inflammatory cytokines
Use of oncolytic viruses in combination with CAR-T cell therapy in pre-clinical and clinical studies
Scientist's achievements in recombinant genetic engineering sciences have led to significant progress in oncolytic viruses' usage. By oncolytic viruses' genome editing, the ability of these viruses to destroy the tumor cells can be altered, and their oncotropic nature can be improved. Inserting the oncolytic viruses into the target cells could turn the cancer cells into cytokine and chemokine factories, thus modifying TME (tumor microenvironment) from an immunosuppressive environment to an immunostimulatory one to facilitate the summoning and induction of the immune cells (such as CAR-T cells) and factors [51]. Tumor cells will try to suppress the immune system, but after contaminating with oncolytic viruses, danger signals are sent, and therefore immune cells such as CD8 + T cells will arrive at the scene and destroy the tumor cells [60]. Until now, many manipulated oncolytic viruses have been used in pre-clinical and clinical steps of researches. The results of using oncolytic viruses and CAR-T cell therapy spontaneously in animal studies have been promising. In the following, we discuss the results of the clinical and pre-clinical studies about CAR-T cell therapy combined with oncolytic viruses.
In a study conducted by Anna Wing et al. on pancreatic ductal carcinoma/colorectal carcinoma, Onc. Ad-EGFR BITE adenovirus, which is armed by EGFR-targeting, a bispecific T-cell engager was used. Concomitant use of this engineered virus and the CAR-T cells containing 4-1BB endodomain and targeting folate receptor alpha (FR-α) antigen will improve the function of the CAR-T cells. This happens because of the BITE secretion of the contaminated cancer cells. Although tumor cells are free of CAR-specific antigens (FR-α in here) but can be targeted and destroyed by the CAR-T cells thanks to BITE secretion, and this is where BITE importance is two folded [19]. Pancreatic ductal carcinoma has a highly immunosuppressive TME and increased Treg cells. So pancreatic tumors TME can disturb T-cell function [61, 62]. In a study relevant to this malignancy, they utilized the TNF-α and IL-2 expressing Onc.Ad-TNF-α/IL-2 oncolytic virus combining with Mesotheline (meso)-specific CAR-T cells containing 4–1 BB endodomain improved the efficiency of the anti-tumor activity of the CAR-T cells (in comparison with using it alone) in mouse models. This improvement in the efficiency of the CAR-T cells could be related to the local expression of the TNF-α and IL-2 in addition to the oncolysis characteristics of these viruses [63]. These cytokines could expand the number of tumor-infiltrating cells in the tumor microenvironment [63, 64].
Efficient animal studies have been performed in the combined oncolytic viruses and CAR-T cell therapy to treat other carcinomas such as head and neck carcinoma and neuroblastoma. Using of the Onc. Ad5Δ24 virus (armed with RANTES chemokine and IL-15 cytokine) along with Ganglioside GD2-specific CAR-T cells to treat the tumors leads to an increase in the attraction and survival of the CAR-T cells in neuroblastoma tumor environment [65]. In research performed by Amanda Rosewell Shaw et al. on head and neck cancer metastasis, a type of binary oncolytic adenovirus named CAdVECIL12p70/αPDL1 was employed in combination with human epidermal growth factor 2 (HER2)-specific CAR-T cells. The construct used in this study encoded the PD-L1 blocking antibody concomitantly with IL-12P70. Local production of the anti-PD-L1 in the tumor site is the advantage of this oncolytic virus [66]. Systemic applying the antibodies against the immune checkpoint blockers like PD-L1 and CTLA-4 can lead to unwanted manifestations such as autoimmunity and even tumor growth. Therefore, it appears that manipulated oncolytic viruses could reduce the inappropriate systemic effects of these treatments by local production of these antibodies [67, 68].
Oncolytic viruses can cooperate with lymphocytes against malignancies, but because there is an immune response against these viruses, therapeutic doses of them to dominate the immune responses, including antibodies, are very high [69, 70]. To overcome this issue, Heather VanSeggelen et al. investigated using CAR-T cells loaded with low-dose oncolytic viruses. The results of this study disclosed that there is no difference in the CAR expression inside virus-loaded CAR-T cells with intact CAR-T cells, and there was no disturbance in the function of manipulated CAR-T cells. It can be said that CAR-T cells successfully transferred the virus to tumor cells [71]. Although this was an in vitro study, the results are auspicious since combining two treatment strategies comes to meaning only when there is no interference between the treatments. According to the results of this study, utilizing the "variable oncolytic virus-loaded CAR-T cells" can be suggested to future pre-clinical researches and survey the results of this novel method in animal models of cancer.
Many clinical trials about the use of oncolytic viruses in tumor treatment are on the line. In 2015, the FDA approved the talimogene laherparepvec (T-VEC) license for melanoma. T-VEC is an engineered HSV-1, which expresses human granulocyte–macrophage colony-stimulating factor (GM-CSF). GM-CSF increases the summoning of the antigen-presenting cells to the tumor environment. T-VEC provokes tumor death with specific proliferation in the tumor cell and stimulates the specific immune system response against the tumor as a secondary function [72]. Applying T-VEC as a combination with chemotherapy [73], radiotherapy [74], and drugs like ipilimumab (anti-cytotoxic T lymphocyte antigen 4 antibody) [75] are available approaches to increase the efficiency of this therapeutic method. Therefore, considering these cases, the T-VEC and CAR T-cell combination can be investigated in the future. However, only one approved clinical trial investigated CAR T and OV combination therapy for HER2-positive tumors (NCT03740256) [76]. Selecting a particular combination of the oncolytic virus and a CAR vector relates to various items, such as the virus's ability to contaminate cells that are expressing CAR antigen.
Tumor and their treatment have been one of the challenges in medical science until now. The FDA approval of two CAR-T cells against hematologic malignancies, tisagenlecleucel-T (Kymriah, Novartis) and axicabtagene ciloleucel (YesCAR Ta, Kite Phama), as well as the first OV (talimogene laherparepvec) for the treatment of melanoma, all are inspiring and significant advances in the field of cancer immunotherapy for the control and cure of an incurable disease. However, issues like possible pathogenicity of viable biologic agents, virus elimination by the immune system, not so high efficacy of CAR-T cell therapy in treating solid tumors, CAR-T cell-induced cytokine storms, and the same obstacles are very complex challenges in the road of clinical development. This review will discuss two cancer treatment approaches: CAR-T cell therapy and using the oncolytic viruses and combination use of them. It is demonstrated in pre-clinical studies and various animal models of cancer that using these treatments concomitantly is more efficient than using them alone. However, further investigations in this field to determine the appropriate virus, proper administration method, and finding possible complications are highly suggested. The combined use of CAR-T cell therapy and the oncolytic viruses can reduce the evading of the virus from immunotherapy. These discoveries enclose that this combined method can cause remarkable evolution in cancer treatment, especially solid tumors.
The data achieved and analyzed during this study are available from the corresponding author on reasonable request.
PMHC:
Peptide-major histocompatibility complex
TAA:
Tumor-associated antigen
PAMP:
Pathogen-associated molecular pattern
DAMP:
Damage-associated molecular pattern'
HSPs:
Heat shock proteins
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Watanabe K, Luo Y, Da T, Guedan S, Ruella M, Scholler J, et al. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. 2018;3(7):e99573. https://doi.org/10.1172/jci.insight.99573.
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Hatem Soliman, M.D., H. Lee Moffitt Cancer Center and Research Institute. (May 20, 2016 - October 28, 2021). Talimogene Laherparepvec in Combination with Neoadjuvant Chemotherapy in Triple Negative Breast Cancer. Identifier NCT02779855. Available from: https://clinicaltrials.gov/show/NCT02779855.
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The authors wish to thank all staff of Applied Virology Research Center, Baqiyatallah University of Medical Science, Tehran, Iran, for their cooperation in implementing experimental procedures and analysis of data.
There was no funding source for this study.
Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Mahdieh Farzanehpour, Ruhollah Dorostkar & Hadi Esmaeili Gouvarchin Ghaleh
Immunology Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Ali Zarezadeh Mehrabadi
Department of Microbiology and Virology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
Fatemeh Roozbahani
Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
Reza Ranjbar
Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
Alireza Shahriary
Mahdieh Farzanehpour
Ruhollah Dorostkar
Hadi Esmaeili Gouvarchin Ghaleh
HE, RD, and AS conceived and designed the study. AZ, FR, RR, and MF wrote the manuscript and arranged the figures and table. HE and RD contributed to reviewing and editing the paper. All authors read and approved the final manuscript.
Correspondence to Hadi Esmaeili Gouvarchin Ghaleh.
Zarezadeh Mehrabadi, A., Roozbahani, F., Ranjbar, R. et al. Overview of the pre-clinical and clinical studies about the use of CAR-T cell therapy of cancer combined with oncolytic viruses. World J Surg Onc 20, 16 (2022). https://doi.org/10.1186/s12957-021-02486-x
Received: 22 September 2021
DOI: https://doi.org/10.1186/s12957-021-02486-x
Chimeric antigen receptor T cells (CAR T cells)
Combined approaches
Oncolytic viruses
Submission enquiries: reginald.medina@springernature.com


text:
Walter Trier fonds
[19--]
David Blackwood fonds
Fonds consists of documentation of David Blackwood's career as a visual artist in Canada. Accumulated content includes exhibition catalogues and related documents, biographical information on David Blackwood, publicity materials, photographs and s...
Blackwood, David
Peggy Gale fonds
Fonds consists of documentation of Peggy Gale's career as an independent writer and curator in Canada with projects in the US, Europe, Brazil, and Japan. Accumulated content includes records of curated exhibitions, publications, photographs and sl...
Gale, Peggy, 1944-
Pleasure Dome fonds
Fonds consists of material produced by Pleasure Dome in Toronto for its programs of film and video exhibitions between 1989 and 2016, including press releases, clippings of notices and reviews, programming records with correspondence, and related ...
Pleasure Dome (Toronto, Ont.)
Micah Lexier Fonds
Fonds consists of the working papers of Micah Lexier. Items include correspondence, sketches, project descriptions and proposals, press clippings, publicity materials, and other documents pertaining to the design and fabrication of artworks.
Lexier, Micah
Sorel Etrog fonds
Fonds consists of the records of the life and work of Sorel Etrog, including his personal, professional and literary correspondence; records of exhibitions and of acquisitions of his work by various galleries and collectors; administrative records...
Etrog, Sorel, 1933-2014
Fonds consists of corporate records of Gallery Moos, including files on artists and associated dealers and galleries, art fair participation and travel, business correspondence, publishing and administrative records and the records of David Moos a...
Moos, Walter, 1926-2013
Robert Fones fonds
[19--]-2011
Fonds consists of Robert Fones' correspondence, journals, sketchbooks, art production materials and files for artworks and public art commissions, unpublished handmade artists books, a set of rubber stamps used for correspondence art, and ephemera...
Fones, Robert
Murray Favro fonds
Fonds contains notes, sketches and plans for artwork by Murray Favro; correspondence with curators, dealers and others; and related documents and ephemera.
Favro, Murray
Suzy Lake fonds
[c.1953]-2010
Fonds consists of Suzy Lake's documentation of her artistic projects and exhibitions, records of her teaching activity at the University of Guelph, trial proofs used in the production of photo murals, and an example of early experimental work by t...
Lake, Suzy, 1947-


I.T. By Me - Remote Support Specialist > Categories > News > Affordable Computer Help Has Arrived!
By way of introduction, my name is Scott Carswell & I have decided, residents of York Region, Richmond Hill in particular, need a more affordable option for resolving, and preventing problems with their personal computers.
I am a certified I.T. Technician and absolutely love solving computer related problems.
I appreciate your visit, feel free to email me with any questions or comments!


text:
Florida Senate - 2012                              (NP)    SB 16
By Senator Braynon
33-00126-12                                             201216__
1                        A bill to be entitled
2         An act for the relief of Ronnie Lopez and Robert
3         Guzman, individually and as co-personal
4         representatives of the Estate of Ana-Yency Velasquez,
5         deceased, and for Ronnie Lopez, Jr., Ashley Lorena
6         Lopez-Velasquez, and Steven Robert Guzman, minor
7         children of Ana-Yency Velasquez, by Miami-Dade County;
8         providing for an appropriation to compensate the
9         estate and the minor children for the death of Ana
10         Yency Velasquez as a result of the negligence of an
11         employee of Miami-Dade County; providing a limitation
12         on the payment of fees and costs; providing an
13         effective date.
15         WHEREAS, Ronnie Lopez, co-personal representative of the
16  Estate of Ana-Yency Velasquez, deceased, is the father of Ronnie
17  Lopez, Jr., age 4, and Ashley Lorena Lopez-Velasquez, age 3, and
18  Ana-Yency Velasquez, deceased, was the mother of Ronnie Lopez,
19  Jr., and Ashley Lorena Lopez-Velasquez, and
20         WHEREAS, Robert Guzman, co-personal representative of the
21  Estate of Ana-Yency Velasquez, deceased, is the father of minor
22  child, Steven Robert Guzman, age 8, and Ana-Yency Velasquez,
23  deceased, was the mother of Steven Robert Guzman, and
24         WHEREAS, on February 23, 2009, a Miami-Dade County Police
25  Officer, when driving his marked police unit through an
26  intersection, failed to obey a posted stop sign and also did not
27  engage his lights or sirens, and
28         WHEREAS, protocol for the Miami-Dade County Police
29  Department requires that lights and sirens be engaged whenever
30  any police vehicle is in pursuit of another vehicle, and
31         WHEREAS, s. 316.271, Florida Statutes, requires that sirens
32  be engaged whenever an authorized emergency vehicle is
33  responding to an emergency or in immediate pursuit of an actual
34  or suspected violator of the law, and
35         WHEREAS, the vehicle driven by the Miami-Dade County police
36  unit was in pursuit of a phantom speeding vehicle at the time of
37  the collision, and
38         WHEREAS, the Miami-Dade County police cruiser crashed into
39  and broadsided the vehicle operated by Ana-Yency Velasquez, then
40  23 years of age and the mother of three minor children, at the
41  intersection of N.W. 112th St. and N.W. 12th Ave., and
42         WHEREAS, the Miami-Dade County police cruiser operated by
43  the officer struck the vehicle driven by Ana-Yency Velasquez
44  with such force that her automobile crashed into the bedroom of
45  a nearby residence, throwing debris from the automobile onto the
46  roof of the residence, and
47         WHEREAS, Ana-Yency Velasquez was killed as a result of the
48  negligence of an employee of Miami-Dade County, Florida, and
49         WHEREAS, mediation of the claims of this matter was held on
50  November 17, 2010, and
51         WHEREAS, at mediation, Miami-Dade County acknowledged that
52  the damages far exceeded the statutory limit of $200,000
53  established under s. 768.28, Florida Statutes, and the
54  representatives of Miami-Dade County agreed and entered into a
55  Mediation Settlement Agreement, and
56         WHEREAS, in the Mediation Settlement Agreement, Miami-Dade
57  County agreed to pay $150,000 to the plaintiffs under the
58  statutory limits on damages, and the remaining $50,000 was paid
59  to the co-personal representatives of the Estate of Ana-Yency
60  Velasquez and to the owner of the house that incurred damage as
61  a result of the crash, and
62         WHEREAS, Miami-Dade County has paid $150,000 to the co
63  personal representatives of the Estate of Ana-Yency Velasquez
64  under the statutory limits of liability set forth in s. 768.28,
65  Florida Statutes, and
66         WHEREAS, Miami-Dade County has agreed in the Mediation
67  Settlement Agreement to actively support the passage of a claim
68  bill in the amount of $1,010,000, NOW, THEREFORE,
72         Section 1. The facts stated in the preamble to this act are
73  found and declared to be true.
74         Section 2. Miami-Dade County is authorized and directed to
75  appropriate from funds of the county not otherwise appropriated
76  and to draw a warrant in the sum of $1,010,000, payable to
77  Ronnie Lopez and Robert Guzman, individually and as co-personal
78  representatives of the Estate of Ana-Yency Velasquez, deceased,
79  for the benefit of Ronnie Lopez, Jr., Ashley Lorena Lopez
80  Velasquez, and Steven Robert Guzman, minor children of Ana-Yency
81  Velasquez, as compensation for the death of Ana-Yency Velasquez
82  as a result of the negligence of an employee of Miami-Dade
83  County.
84         Section 3. The amount paid by Miami-Dade County pursuant to
85  s. 768.28, Florida Statutes, and the amount awarded under this
86  act are intended to provide the sole compensation for all
87  present and future claims arising out of the factual situation
88  described in the preamble to this act which resulted in the
89  death of Ana-Yency Velasquez. The total amount paid for
90  attorney's fees, lobbying fees, costs, and similar expenses
91  relating to this claim may not exceed 25 percent of the total
92  amount awarded under section 2 of this act.
93         Section 4. This act shall take effect upon becoming a law.


text:
CCPA Compliance — A Guide for Fintech
The global wave of increased privacy regulations hits California on January 1, 2020 when the California Consumer Privacy Act (CCPA) takes effect.
The CCPA provides broad-reaching data privacy rights to California residents, and any for-profit business serving them must comply if it meets certain thresholds. Many fintech companies are already large enough to qualify (they have $25M in annual gross revenue or 50K California customers) or have plans to grow to that size. Big Tech companies like Facebook and Amazon that are eyeing the financial services sector also fall into this category.
For the hundreds of fintech companies doing business in the Golden State, this may be their first encounter with privacy compliance. If their customer base is confined to the U.S., they aren't subject to the EU's General Data Protection Regulations (GDPR), which European and global corporations have been grappling with since May 2018. They may also not be subject to national banking regulations like the Gramm-Leach-Bliley Act (GLBA).
So the moment has arrived for fintech to come to terms with privacy compliance.
Download CCPA Compliance: A Systematic Approach to Consumer Privacy
Why does CCPA compliance matter to fintech?
The CCPA has a number of implications that should make fintech companies sit up and pay attention.
The consequences of noncompliance can be costly
The CCPA includes provisions for fines of $2,500 per unintentional violation and $7,500 per intentional violation, per customer affected. Consumers affected by data breaches can also sue companies if the stolen data was not encrypted or redacted before the breach, with awards of $750 per customer.
Fines under the GDPR have been relatively modest to date, but indications are that the CCPA will be rigorously enforced. The law firm Cooley speculated that there is a high risk of enforcement by an experienced attorney general and plaintiffs' bar.
Compliance increases customer trust
Fintech companies are playing catch-up to established financial institutions (FIs) when it comes to earning a trusted reputation with customers. Achieving compliance demonstrates to the public that a fintech takes privacy seriously. And conversely, noncompliance can cause reputational damage at a crucial time in a fintech's growth.
Data privacy issues related to tech companies
Anupam Sahai, VP of security intelligence firm Cavirin, stated that the CCPA "is looking to stop companies that have been leveraging consumer information (sometimes without the consumer's knowledge) to obtain financial benefit, which may not be aligned with the consumer's understanding of the information usage. These types of organizations are: internet providers delivering value added via over-the-top (OTT) services (AT&T DirecTV, Verizon Oath, etc.); social media firms; advertisers; online retailers; and non-banks (fintech firms)."
As noted by John Stephens of the American Bar Association, "The legislation specifically cites the March 2018 disclosure of the misuse of personal data by Cambridge Analytica. The legislation also references recent congressional hearings that followed which highlighted the fact that any personal information shared on the internet can be subject to considerable misuse and theft."
Since fintech has been identified as an industry of concern for data privacy, it will likely attract even greater scrutiny around compliance.
Fintech needs to plan now for robust scalable solutions
Privacy compliance touches on many aspects of a company's operations, including data collection, storage and use. In order to achieve and maintain compliance as a company grows, fintech should consider automated, digital solutions. These solutions provide "privacy by design" that can scale up without sacrificing performance, and they offer better security and a lower total cost. Those solutions could include electronic identity verification, customer identity and access management, and platforms for sales, marketing and support.
How the CCPA applies to fintech
We've pulled out a few highlights from the CCPA that are particularly relevant to fintech.
The definition of personal information goes beyond that of current state regulations
The CCPA defines "personal information" as any information that "identifies, relates to, describes, is capable of being associated with, or could reasonably be linked, directly or indirectly, with a particular consumer or household." This definition includes info such as the following:
The Data Protection Report noted that "By removing the name requirement and instead including specific data elements such as IP address, browser history and geolocation data as PI, the CCPA requires companies to reexamine how data is tagged and risks related to data is analyzed and mitigated."
CCPA does not override KYC and AML requirements
As a state law, the CCPA does not take precedence over national laws like the Bank Secrecy Act (BSA) or the Patriot Act. If a company has obligations around notice and access under KYC/AML regulations, it must continue to meet them, even if they contradict the CCPA requirements.
CCPA and GLBA have some overlap and exemptions
Both acts address the handling of personal information, and the CCPA exempts some personal information that is subject to the GLBA, so they need to be considered together. This is yet another area that demonstrates the necessity of good compliance officers and lawyers.
Importance of identity and age verification
Given the sensitivity of financial accounts and information, fintech companies should make sure that they are verifying the identity of individuals who, for example, request that an account and data be deleted. The CCPA requires that businesses make a good faith effort to verify subject access requests, similar to the GDPR. Companies may also need to verify ages of consumers under 16 in order to make sure they are collecting the appropriate consent from parents.
Given that the CCPA is not as complex or far-reaching as the GDPR, it could be an easier point of entry for U.S. fintech companies that haven't been subject to stringent privacy regulations previously. Easier doesn't mean easy, though, and starting now will help make sure that fintech companies properly protect customer data so they can continue to scale with confidence.
Learn More: Download CCPA Compliance: A Systematic Approach to Consumer Privacy
Learn more about the CCPA requirements and which business processes they affect. Get familiar with the considerations for achieving compliance with the CCPA and how to develop a systematic approach to privacy.
California compliance Privacy
A Snapshot of Digital ID in the 10 Most Populous Countries — Part 1
Political Ads in Canada — New Registry Requirements


LOS ANGELES (WGNTV) -- Well, that wasn't very nice.
Cara Viramontes logged in to check her itinerary and saw a message that said, "F*** you!" She then discovered her family's travel reservation had been canceled.
"Everyone I show, they laugh and think it's a joke," she told Los Angeles' KCBS. "No one can believe a company as credible as Expedia would ever do something like this."
Viramontes has sneaking suspicion that she knows why the comment was directed at her. She'd complained about being charged for travel insurance for her 8-month-old son even though he didn't need an airline ticket and was going to sit on her lap.
She said the employee she talked to wasn't helpful and wouldn't let her speak to a supervisor when she asked to do so. Viramontes said she was "honest" when responding to a survey about her customer service experience.
Viramontes said the company hadn't compensated her for the $600 she paid for the plane tickets and told her she'd have to pay $200 to book another flight.
She didn't receive a response about the foul message until the TV station intervened. In a statement, the company said it was taking the matter seriously and investigating the actions of its employees.
Expedia said it would rebook Viramontes' flights, refund her money and give her a $500 voucher.


When cousin Savvy gives you the good word.
Below is an excerpt from my work in progress, WINNER TAKES ALL. This scene takes place right after Divina Langley and Grant Easton first meet at the recreation center where her cousin, Savannah Hawkins, works. IDK, I think they might kinda, sorta like each other, lol!
A ruckus on the court brought the cheering crowd to their feet, drawing Divina and Savvy's attention to it.
An embarrassed opponent was glaring after Grant from underneath the basketball hoop as Grant ran, smirking, back down the court. He glanced Divina's way and awareness shot through her when Grant pointed toward the scoreboard, then back at her and winked. Divina stifled a proud smile when she saw his team was now up by eight.
"Do they have actual names?" Divina peeped across the gym to see another tall guy whose attractiveness rivaled yet resembled his cousin's, letting two girls do his hair as he called out advice to his team members.
Divina did a slow evaluation of her surroundings and met numerous challenging glares from the diverse female population in attendance. The ratio of females to males in attendance was at least ten to one.
Divina watched the words leave her cousin's mouth, listened to what she was saying, and even managed to process it. Her reasoning sounded logical, and Divina was certain that Savvy wouldn't lie to her. But her eyes involuntarily sought out Grant again, and found him at the end of the court, using the bottom half of his shirt to wipe off the sweat dripping from his face. The action exposed a rippling six-pack that made Divina's mouth go dry, then flood with drool. Grant dropped his shirt and their eyes locked. Her heart refused to heed Savvy's warnings as currents of attraction and expectation sizzled between them, seductively luring Divina further under Grant's spell. In the months to come, she would soon discover the problem with logic. It was the heart's worst enemy.
I hope you enjoyed another sneak peek at Divina & Grant, along with some of the Baxter Park crew!
Next postGood things come to those who…break the rules?
Love it!! So excited for Grant and Davina's story. As always D.A. your stories have us anticipating and hungry for more. Thank you again for sharing your books and gift of writing with us.
You're welcome, Carol! Thank you and I'm glad you enjoyed it!
Yesss! He's already in my top 5!
Loving the candy bar references for Frick and Frack! Both Savvy and Lincoln are silently beeping on my radar screen. Ever since Second Chances, you've peaked my interest with Grant & Divina. Forever Yours, hinted at perhaps a crack in their barrier wall. i've wanted to know more of these two!! Can hardly wait for June 5, 2018!Whether it is Kismet Cove, Baymoor or Whiskey Row series every couple, characters (Spring Chickens are my favorite gals) and story's journey is a pleasurable treat what is worth repeating.Looking forward to discovering Lincoln Park as well. Congrats on your blog too. Thanks for sharing a little more of Grant and Divina.


"Couldn't wait to give this place 5 stars! We went for lunch, i had green curry! It was yummy and came with free chicken/rice soup. The thai iced coffee was amazing as well. Service was so quick, our food came out within 5 minutes. Prices are very reasonable. We will definitely be coming back for dinner!"
"Solid. Great pricing, clean, quick and nice service. The food is awesome as well. Will definitely be back."