Day: 01/30/2023

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A

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Abstract

Background

Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor–imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear.

Methods

We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health.

Results

In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P=0.03), and joint health (P=0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected.

Conclusions

In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health.

Source: NEJM

New Class of Factor VIII Replacement Therapy Prevents Bleeds in Severe Hemophilia A

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Weekly dosing with efanesoctocog alfa reduced annualized bleeding rate by 77%

A computer rendering of red blood cells and platelets in a blood vessel.

Treatment with investigational efanesoctocog alfa (formerly BIVV001) — a new class of factor VIII replacement therapy — prevented bleeding episodes in patients with severe hemophilia A, according to results from the phase III XTEND-1 trialopens in a new tab or window.

Among 133 patients, almost all males, who received once-weekly prophylaxis with efanesoctocog alfa 50 IU/kg for 52 weeks (group A), the median annualized bleeding rate was 0 (interquartile range 0-1.04), and the estimated mean annualized bleeding rate was 0.71 (95% CI 0.52-0.97), reported Annette von Drygalski, MD, PharmD, of the University of California San Diego, and colleagues.

In an analysis involving a subgroup of 78 patients, switching from a pre-study standard-care factor VIII prophylaxis regimen to efanesoctocog alfa decreased the mean annualized bleeding rate from 2.96 to 0.69, a reduction of 77%, which showed superiority over pre-study prophylaxis (annualized bleeding rate ratio 0.23, 95% CI 0.13-0.42, P<0.001), they noted in the New England Journal of Medicineopens in a new tab or window.

In a smaller group of 26 men who received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis for 26 weeks (group B), the annualized bleeding rate decreased when patients switched from on-demand treatment to prophylaxis (21.42 versus 0.69).

Overall, 80% of group A and 85% of group B patients had no spontaneous bleeding episodes during the prophylaxis periods. When bleeding events did occur, a single injection of efanesoctocog alfa 50 IU/kg provided effective resolution for 97% of events.

Of note, von Drygalski and team said that once-weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU/dL for approximately 4 days after administration and of 15 IU/dL at day 7.

Furthermore, prophylaxis with efanesoctocog alfa for 52 weeks improved physical health (P<0.001), pain intensity (P=0.03), and joint health (P=0.01).

“Collectively, these results show that by maintaining high sustained factor VIII activity, once-weekly efanesoctocog alfa provided substantial improvements in clinical outcomes and quality of life for patients with severe hemophilia A,” the authors wrote.

Efanesoctocog alfa is currently under review with the FDAopens in a new tab or window for the treatment of hemophilia A, with a target action date of February 28, according to developers Sanofi and Sobi.

Breaking Through the von Willebrand Factor ‘Ceiling’

The ability to provide high, sustained factor VIII activity in patients with hemophilia A has been constrained by the von Willebrand factor-imposed half-life ceiling.

While normalizing factor VIII levels helps protect patients with hemophilia A from spontaneous and traumatic bleeding, thus preserving joint health, von Drygalski and colleagues pointed out that the interaction between factor VIII and endogenous von Willebrand factor limits the half-life of current factor VIII replacement products to 8 to 19 hours.

“Therefore, maintaining factor VIII levels in the normal range (50 to 150 IU per deciliter) or levels that are close to normal (>40 to <50 IU per deciliter) with currently available factor VIII therapies requires frequent administration, which confers a substantial treatment burden on people with hemophilia and their caregivers,” they wrote.

Efanesoctocog alfa circulates independently of endogenous Von Willebrand factor, is designed to overcome that half-life ceiling, and thus extends protection from bleeds with once-weekly dosing. In this study, efanesoctocog alfa had a long geometric mean half-life of 47.0 hours (95% CI 42.3-52.2).

In an editorial accompanying the studyopens in a new tab or window, Cindy Leissinger, MD, of Tulane University School of Medicine in New Orleans, said a major advantage of efanesoctocog alfa “is its value as a true factor VIII replacement that can be used to treat acute bleeding and can be measured by standard laboratory assays to allow for monitoring and dose adjustments when needed.”

She also pointed out that while trials of factor VIII gene therapies also show prolonged production of factor VIII, the latest results suggest that factor VIII production in most patients gradually declines over a few years to trough levels demonstrated with weekly efanesoctocog alfa.

“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner — a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” Leissinger concluded.

Study Details

For this multicenter study, previously treated patients ages 12 years and older with endogenous factor VIII activity of less than 1 IU/dL (<1%) or a documented genotype known to produce severe hemophilia A were included.

Patients were excluded if they had a positive test for factor VIII inhibitor at screening or a history of a positive inhibitor test, clinical signs or symptoms of a decreased response to factor VIII, other known coagulation disorders, a history of hypersensitivity or anaphylaxis to factor VIII therapies, or major surgery within 8 weeks before screening.

Among the 133 patients in group A, mean age was 33.9 years, 99% were males, 53% were white, and 22% were Asian. Of those with evaluable data during the efficacy period, 65% had no bleeding episodes, while 93% had 0-2 bleeding episodes.

Of the 26 patients in group B, mean age was 42.8, all were men, and all were white.

A total of 362 bleeding events occurred during the study, with the majority (74%) in group B during the on-demand treatment period.

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study

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Abstract

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on ‘cold’ or ‘hot’ cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the ‘blunting’ effect often reported by patients with MDD treated with SSRIs.

Introduction

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter implicated in several cognitive and affective brain functions [1]. Drugs that target serotonin transmission, such as selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatments for many neuropsychiatric disorders such as major depressive disorder (MDD), obsessive-compulsive disorder (OCD) and anxiety [2]. Understanding the modulatory role of serotonin on cognition and reinforcement learning is particularly important [3].

Many studies examining the modulatory effects of serotonin on cognition have been conducted in experimental animals [4,5,6]. In rats, impairing serotonin function disrupted reversal learning, whereas enhancing serotonin function improved reversal learning [4]. In marmoset monkeys, targeted neurotoxic serotonin depletion of the orbito-frontal cortex, but not of the caudate nucleus, consistently produced reversal deficits [5, 6]. Marmosets have also shown reduced reinforcement sensitivity following serotonin depletion [7].

In humans, the modulatory effects of serotonin on cognition have largely been examined through acute dietary tryptophan depletion (ATD) [8,9,10,11,12,13,14,15,16,17,18], or through acute SSRI administration [19,20,21,22,23]. ATD has been shown to affect measures of both ‘cold’ (rational and non-emotional), and ‘hot’ (social and emotional) cognition [13,14,15,16,17,18]. Specifically, ATD induces ‘waiting’ impulsivity and impulsive behaviours, impairs goal-directed behaviour and shifts behavioural control toward habitual responding in appetitive conditions, but goal-directed in aversive conditions [10,11,12]. Effects of ATD have also been seen on reinforcement behaviour [13], reversal learning [9, 14], learning and memory [15], affective and social cognition [9, 16, 17] and moral judgement [18]. Studies examining the acute administration of SSRIs have shown impaired probabilistic learning [19, 20], and impaired cognitive flexibility [20], but increased long-term memory recall [21], emotion recognition [22], and harm aversion for moral judgements [23]. One study showed that response inhibition improved with SSRI administration [20], whereas another showed no effect [19]. Taken together, a wide range of cognitive functions is affected by serotonin modulation in healthy volunteers.

Given that SSRIs are administered chronically in the treatment of neuropsychiatric disorders, it is particularly important to understand the long-term effects of SSRI administration on cognition. Currently, only a few studies have examined SSRIs administered sub-chronically, over approximately 7 days [24, 25]. Short-term administration of antidepressants may ameliorate the negative biases in information processing that are often present in mood and anxiety disorders [24]. A recent study examined both the acute and short-term effects of SSRIs. The results showed that acute administration did not affect reinforcement learning, but short-term administration resulted in increased learning from punishment, with reduced learning from reward [25]. However, there was no statistical difference in performance between the acute and short-term administration, and therefore these results must be interpreted with caution. In addition, studies with patients with MDD have shown that SSRIs impair learning from negative feedback, while having negligible effect on learning from positive feedback [26]. These findings demonstrate the difficulty in understanding the modulatory role of SSRI on various cognitive and motivational processes. One study gave a tryptophan-rich diet to middle-aged healthy volunteers for 19 days and showed that emotional bias to negative stimuli was reduced [27].

Understanding the acute effects of SSRIs on cognitive processes in healthy volunteers and patients with MDD is complex. This may be due to the differing possible pre- and post-synaptic actions [28]. In addition, there is some evidence that the neuroplasticity effects of SSRIs emerge only after more chronic administration (14–21 days) [29, 30]. As such, the chronic administration of SSRI may provide more robust results. Importantly, chronic SSRI administration is an experimental model that better mimics a treatment model of MDD. In addition, to our knowledge, no studies have examined the more chronic effects of SSRIs on a wide range of cognitive measures.

Escitalopram is the active S-enantiomer of the racemic SSRI citalopram (RS-citalopram) [31]. By removing the R enantiomer and only containing the pure active S enantiomer the effects of the drug are improved [28]. For example, there are no higher dose restrictions, and it also makes the lowest dose more efficacious [28]. In addition, Escitalopram shows very high selectivity for the serotonin transporter and is thus the best choice for testing pharmacologic actions of SSRIs [28, 31]. Moreover, escitalopram is an effective treatment for moderate-to-severe major depressive disorder (MDD) and is one of the best-tolerated SSRIs [28, 31].

In the present study, we used a double-blind placebo-controlled design to examine the effects of the SSRI escitalopram administered on average for 26 days, on a comprehensive set of measures of ‘cold’ and, ‘hot’ cognition, including decision-making and computational measures of reinforcement learning. We hypothesised that SSRI treatment would affect reinforcement-related behaviour, probabilistic reversal learning, and response inhibition.

Discussion

To our knowledge, this is the first study to determine the effects of chronic escitalopram administration on a broad range of measures of ‘cold’, and ‘hot’ cognition, including reinforcement learning in healthy volunteers. In this double-blind placebo-controlled study, a relatively large group of healthy volunteers received either escitalopram or placebo for an average of 26 days. The novel and important finding was that escitalopram had the specific effect of reducing reinforcement sensitivity in two independent tests, but had no effects on other measures of ‘cold’ or ‘hot’ cognition.

Reinforcement behaviour

The reinforcement sensitivity parameter, as modelled here, governs the degree to which a participant is driven by their reinforcement history [35]. Using this innovative approach, we found reduced reinforcement sensitivity in the escitalopram group in two different test paradigms, one on model-based vs model-free behaviour (Fig. 2) and the other in a standard PRL task. A previous study examining how reinforcement is influenced by serotonergic modulation showed that acute tryptophan depletion decreased reinforcement sensitivity, by impairing the representation of reward outcome value [13]. This was only the case for reward sensitivity, and there was no effect on punishment sensitivity [13]. In the present study, we did not find any effects on reward or punishment learning rates, whereas one study showed increased reward learning neural signals, specifically related to prediction error, following 2 week SSRI administration [39]. However, it is important to note the different methodologies used in these studies, which makes a direct comparison of the results difficult.

Importantly, our results are of considerable relevance when considering the patients’ experience of taking SSRIs chronically. Patients’ often report experiencing a ‘blunting’ effect [40,41,42]. This blunting effect has also been demonstrated for rewarding and punishing stimuli. Specifically, participants receiving 7 days of SSRI had lower neural processing of both rewarding and aversive stimuli [43]. In light of our own results, it is possible that the clinical effectiveness of SSRIs for MDD is due to this reduced negative affect. However, if indeed positive affect is also reduced, then this would lead to a more general blunting effect, as often reported by patients taking chronic SSRIs. This is supported by the present study, in which lower reinforcement sensitivity would suggest decreased control over behaviour by both rewarding and punishing stimuli. This may also be further supported by our findings that the escitalopram group had significantly higher dysfunction on the dimensions/phases corresponding to orgasm/completion on the CSFQ-14. It is possible that participants taking escitalopram experience greater sexual dysfunction due to experiencing less pleasure, which has been supported by previous reports [44]. However, this is speculative as there are other mechanisms that may explain this effect [45].

‘Hot’ cognition

Our results showed no effects on other measures of ‘hot’ cognition. Studies have previously shown that acute and sub-chronic SSRI intervention affects emotion recognition, specifically for recognition of fear and happiness [22]. In our chronic administration study, we did not examine emotion recognition in each emotion, but rather examined affective bias, which was not affected significantly by escitalopram. We also did not find any effects of escitalopram on moral judgements as previously reported following acute treatment [18, 23].

‘Cold’ cognition

Our results showed no significant effects on any measures of ‘cold’ cognition, thus contrasting with some of our previous data obtained following acute administration [20]. Previous studies manipulating serotonin acutely have shown alterations in both ‘cold’ and ‘hot’ cognitive measures [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. However, it is important to note that our study examined SSRI administration over a longer time period, which has not previously been much studied in the context of human cognition. Contrasting with the present findings Skandali and colleagues [20], who used similar neuropsychological tests, showed that participants administered escitalopram acutely made more errors to criterion during Stage 1 and exhibited increased lose-shifting after misleading negative feedback in the PRL task. However, they did not conduct the same hierarchical Bayesian modelling employed in the present study. Such an analysis of the Skandali et al. [20] similarly shows reduced reinforcement sensitivity in the escitalopram group compared to placebo controls (unpublished findings). In addition, in the present study there was no effect of escitalopram on performance of the 3D-IED task, suggesting that this result may be specific to learning when there is greater uncertainty, as the 3D-IED is deterministic and the PRL is probabilistic in nature. We showed no effect of escitalopram on response inhibition, whereas Skandali et al. [20] showed that acute escitalopram improved stop-signal reaction time. However, in line with our results, Chamberlain et al. [19] showed no acute effect of the SSRI citalopram on response inhibition.

There are a number of points to note when interpreting the results from the present study. First, it is important to acknowledge the differences between acute and chronic SSRI administration. Previous literature has suggested that neuro-adaptive changes might represent homoeostatic mechanisms by which the brain regulates neurotransmission in response to the drug [46, 47]. This may suggest that the acute effects are not as robust as longer-term effects where this mechanism would have stabilised. In addition, acute administration of SSRIs does not seem to affect neuroplasticity, which does occur when administered chronically [29, 30]. Moreover, the synaptic mechanism of action for acute and chronic SSRI administration differs [28, 48]. A meta-analysis showed that within the first week of SSRI administration, 5-HT concentrations drop, which then increases over the following two weeks of administration, although this does vary slightly in different regions of the brain [48]. We chose the duration of 3 weeks because this duration is associated with clinical benefits in patients with MDD and with translational studies of neuroplasticity effects. However, we cannot rule out that neuroplasticity effects might be greater with a longer duration of escitalopram.

Second, the approaches for induction of changes in serotonin vary and this could result in the inconsistent findings. For example, previous studies manipulating serotonin acutely with different methods and using the same PRL task, showed inconsistent results using conventional behavioural measures [9, 19, 20]. It should be noted that currently there is no way to reliably determine interstitial serotonin concentrations non-invasively in humans, which means that interpretation of the manipulations must be inferential. Finally, it is likely that the escitalopram effects are less discernible in our cognitively high-performing (average IQ > 110) healthy volunteers than in patients with MDD. Studies on MDD have found that SSRI intervention often normalises abnormal neural processing [49,50,51,52], which in turn improves cognitive functioning and at a later time point, mood [52]. As healthy individuals are cognitively intact, it is possible that the effects may be different from those in patients with MDD. Differential effects on cognition and mood can be seen when studies are conducted with healthy volunteers or patients with MDD [8, 53]. As such the mechanism of SSRIs may be more restorative in MDD, which is unnecessary in healthy individuals. Given that SSRIs are chronically administered to patients with neuropsychiatric disorders, the present results are more clinically relevant than those of acute studies.

One possible limitation of the study was that there was a significant difference in guessing group allocation. However, the escitalopram group were at chance level for guessing group allocation (53% guessing correctly) and over 15% of the placebo group guessed they were on active substance. It is difficult to know how our results on guessing group allocation compares with other studies, as this measure is frequently not reported in the literature. The results are unlikely to have been affected by this, given the lack of cognitive changes and specificity of the effect.

Our results, importantly, showed a specific significant effect on reinforcement sensitivity, where escitalopram reduced reinforcement sensitivity, which may in part be explanatory for the blunting effect often reported by patients receiving chronic SSRI treatments. This study also highlights the need for future studies to examine chronic administration of SSRIs beyond 21 days. In addition, future studies should examine the chronic effects of SSRI administration on a similar extensive battery including ‘cold’, and ‘hot’ cognition, particularly reinforcement behaviour in patients with neuropsychiatric disorders such as MDD or OCD.

Conclusion

In contrast with previous reports on the acute effects of SSRI administration, we did not find any significant effects on ‘cold’ cognitive measures after more chronic administration (mean 26 days). Using an innovative computational modelling approach, we did find significant effects specific to reinforcement learning; chronic escitalopram reduced reinforcement sensitivity compared to placebo. These novel findings provide strong evidence for a key role of serotonin in reinforcement learning. The results have important clinical implications as they may reflect the blunting effect often reported by patients with neuropsychiatric disorders receiving chronic SSRI treatment.

Source: Nature

Older People With Type 2 Diabetes See Growing Cancer Burden

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Has cancer overtaken CVD as a leading cause of death in people with T2D?

A photo of a senior man checking his blood sugar with a glucose meter at home.

Older people with type 2 diabetes faced a higher burden of cancer mortality in recent years, according to a U.K. study.

In a cohort of over 137,000 individuals with type 2 diabetes, all-cause mortality rates dropped among all age groups from 1998-2018, reported Suping Ling, PhD, of the University of Leicester in England, and colleagues.

However, this was juxtaposed by an increase in cancer-related morality rates for people ages 75 and 85 with type 2 diabetes, they wrote in Diabetologiaopens in a new tab or window.

During the median follow-up of 8.4 years, those ages 75 with diabetes saw a 1.2% average annual percentage change (AAPC) in cancer mortality rate, while those ages 85 saw a 1.6% bump each year. On the other hand, those ages 55 and 65 saw a respective 1.4% and 0.2% annual drop in cancer mortality.

Ling’s group examined who was most impacted by this rising cancer mortality rate, and reported that people with morbid obesity (BMI 35-plus) saw one of the highest annual increases of 5.8%. Comparatively, those with a normal body weight (BMI 18.5-24.9) with type 2 diabetes only saw an average 0.7% increase.

Additionally, there was a 1.5% AAPC in cancer mortality for women versus a 0.5% increase for men. The authors noted that “[a]ll-cancer mortality rates and proportions of cancer deaths were higher in men than women for most of the 1998-2018 period, with the gap in both rates and proportions being smaller around 2012-2014 and widening since 2014.”

There also appeared to be an increasing trend in cancer mortality rates for former or current smokers (0.6% and 3.4%, respectively), as well as white individuals (2.4%), whereas downward trends were seen for nonsmokers (-1.4%) and other ethnic groups (-3.4%).

And those living in the least deprived areas saw a 1.5% AAPC compared with a 1% increase for those living in the most deprived areas.

Certain cancer-specific mortality trends emerged among this population with diabetes. Compared with the general population, there were significantly higher standardized mortality ratios (SMRs) for several cancer types among people with type 2 diabetes from 1998-2018:

  • Colorectal: SMR 2.40 (95% CI 2.26-2.54)
  • Pancreatic: SMR 2.12 (95% CI 1.99-2.25)
  • Liver: SMR 2.13 (95% CI 1.94-2.33)
  • Endometrial: SMR 2.08 (95% CI 1.76-2.44)
  • Lung: SMR 1.04 (95% CI 1.00-1.08)
  • Breast in women: SMR 1.09 (95% CI 1.01-1.18)

“The prevention of cardiovascular disease has been, and is still considered, a priority in people with diabetes. Our results challenge this view by showing that cancer may have overtaken cardiovascular disease as a leading cause of death in people with type 2 diabetes,” stated Ling’s group.

“Cancer prevention strategies therefore deserve at least a similar level of attention as cardiovascular disease prevention, especially for colorectal, pancreatic, liver and endometrial cancer, whose mortality rates were substantially higher in individuals with type 2 diabetes than in the general population,” they added.

“Persistent inequalities in cancer mortality rates by sociodemographic factors and widening disparities by smoking status suggest that tailored cancer prevention and detection strategies are needed,” they said. “For example, some subgroups such as smokers experienced not only higher mortality rates but also increasing mortality trends during the study period.”

For the population-based study, the researchers drew upon data on 137,804 newly diagnosed adults, ages 35 and older, with type 2 diabetes in the Clinical Practice Research Datalink. Those with type 1 diabetes were excluded.

The average BMI was 30.6, 55% were men, and 83% were white. Nearly half were nonsmokers and about a third were ex-smokers.

CRISPR cancer trial success paves the way for personalized treatments

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‘Most complicated therapy ever’ tailors bespoke, genome-edited immune cells to attack tumours.

Molecular model of CRISPR-CAS9 gene editing complex in red, yellow and blue colours

The CRISPR–Cas9 complex (blue and yellow) can precisely cut DNA (red)

A small clinical trial has shown that researchers can use CRISPR gene editing to alter immune cells so that they will recognize mutated proteins specific to a person’s tumours. Those cells can then be safely set loose in the body to find and destroy their target.

It is the first attempt to combine two hot areas in cancer research: gene editing to create personalized treatments, and engineering immune cells called T cells so as to better target tumours. The approach was tested in 16 people with solid tumours, including in the breast and colon.Landmark CRISPR trial shows promise against deadly disease

“It is probably the most complicated therapy ever attempted in the clinic,” says study co-author Antoni Ribas, a cancer researcher and physician at the University of California, Los Angeles. “We’re trying to make an army out of a patient’s own T cells.”

The results were published in Nature1 and presented at the Society for Immunotherapy of Cancer meeting in Boston, Massachusetts on 10 November.

Tailored treatments

Ribas and his colleagues began by sequencing DNA from blood samples and tumour biopsies, to look for mutations that are found in the tumour but not in the blood. This had to be done for each person in the trial. “The mutations are different in every cancer,” says Ribas. “And although there are some shared mutations, they are the minority.”

The researchers then used algorithms to predict which of the mutations were likely to be capable of provoking a response from T cells, a type of white blood cell that patrols the body looking for errant cells. “If [T cells] see something that looks not normal, they kill it,” says Stephanie Mandl, chief scientific officer at PACT Pharma in South San Francisco, California, and a lead author on the study. “But in the patients we see in the clinic with cancer, at some point the immune system kind of lost the battle and the tumour grew.”

After a series of analyses to confirm their findings, validate their predictions and design proteins called T-cell receptors that are capable of recognizing the tumour mutations, the researchers took blood samples from each participant and used CRISPR genome editing to insert the genes encoding these receptors into their T cells. Each participant then had to take medication to reduce the number of immune cells they produced, and the engineered cells were infused.CRISPR ‘cousin’ put to the test in landmark heart-disease trial

“This is a tremendously complicated manufacturing process,” says Joseph Fraietta, who designs T-cell cancer therapies at the University of Pennsylvania in Philadelphia. In some cases, the entire procedure took more than one year.

Each of the 16 participants received engineered T cells with up to three different targets. Afterwards, the edited cells were found circulating in their blood, and were present in higher concentrations near tumours than non-edited cells had been prior to the treatment. One month after treatment, five of the participants experienced stable disease, meaning that their tumours had not grown. Only two people experienced side effects that were probably due to the activity of the edited T cells.

Although the efficacy of the treatment was low, the researchers used relatively small doses of T cells to establish the safety of the approach, says Ribas. “We just need to hit it stronger the next time,” he says.

And as researchers develop ways to speed up the therapies’ development, the engineered cells will spend less time being cultured outside of the body and could be more active when they are infused. “The technology will get better and better,” says Fraietta.

A solid start

Engineered T cells — called CAR T cells — have been approved for the treatment of some blood and lymph cancers, but solid tumours have posed a particular challenge. CAR T cells are effective only against proteins that are expressed on the surface of tumour cells. Such proteins can be found across many blood and lymph cancers, which means there is no need to design new T-cell receptors for each person with cancer.CRISPR treatment inserted directly into the body for first time

But common surface proteins have not been found in solid tumours, says Fraietta. And solid tumours provide physical barriers to T cells, which must circulate through the blood, travel to the tumour and then infiltrate it to kill the cancer cells. Tumour cells also sometimes suppress immune responses, both by releasing immune-suppressing chemical signals and by using up the local supply of nutrients to fuel their rapid growth.

“The environment around a tumour is like a sewer,” says Fraietta. “T cells are rendered less functional as soon as they hit the site.”

With this initial proof of concept in hand, Mandl and her colleagues hope to be able to engineer T cells not only to recognize cancer mutations, but also to be more active near the tumour. Mandl says there are several potential ways to toughen up T cells, for example by removing the receptors that respond to immunosuppressive signals, or by tweaking their metabolism so that they can more easily find an energy source in the tumour environment.

Such elaborate designs could be feasible thanks to recent technological advances in using CRISPR to edit T cells, says Avery Posey, who studies cell and gene therapies for cancer at the University of Pennsylvania. “It’s become incredibly efficient,” he says. “We’ll see very sophisticated means of engineering immune cells within the next decade.”

Nature

The race to supercharge cancer-fighting T cells

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With a slew of tools to trick out immune cells, researchers are expanding the repertoire of CAR-T therapies.

Cartoon of an anthropomorphised T-cell driving a hot rod at speed with fire and smoke coming out of the exhaust

Crystal Mackall remembers her scepticism the first time she heard a talk about a way to engineer T cells to recognize and kill cancer. Sitting in the audience at a 1996 meeting in Germany, the paediatric oncologist turned to the person next to her and said: “No way. That’s too crazy.”

Today, things are different. “I’ve been humbled,” says Mackall, who now works at Stanford University in California developing such cells to treat brain tumours. The US Food and Drug Administration approved the first modified T cells, called chimeric antigen receptor (CAR)-T cells, to treat a form of leukaemia in 2017. The treatments have become game changers for several cancers. Five similar products have been approved, and more than 20,000 people have received them. A field once driven by a handful of dogged researchers now boasts hundreds of laboratory groups in academia and industry. More than 500 clinical trials are under way, and other approaches are gearing up to jump from lab to clinic as researchers race to refine T-cell designs and extend their capabilities. “This field is going to go way beyond cancer in the years to come,” Mackall predicts.CRISPR cancer trial success paves the way for personalized treatments

Advances in genome editing through processes such as CRISPR, and the ability to rewire cells through synthetic biology, have led to increasingly elaborate approaches for modifying and supercharging T cells for therapy. Such techniques are providing tools to counter some of the limitations of current CAR-T therapies, which are expensive to make, can have dangerous side effects, and have so far been successful only against blood cancers. “These techniques have expanded what we’re able to do with CAR strategies,” says Avery Posey, a cancer immunology researcher at the University of Pennsylvania in Philadelphia. “It will really take this type of technology forward.”

Even so, the challenge of making such a ‘living drug’ from a person’s cells extends beyond complicated designs. Safety and manufacturing problems remain to be addressed for many of the newest candidates. “There’s an explosion of very fancy things, and I think that’s great,” says immunologist Michel Sadelain at the Memorial Sloan Kettering Cancer Center in New York City. “But the complexity cannot always be brought as described into a clinical setting.”

Revved up and ready to go

CAR-T therapies capitalize on the activities of T cells, the immune system’s natural hunters that prowl through the body looking for things that don’t belong. Foreign cells, or those infected with a virus, express unusual proteins that serve as a beacon to T cells, some of which release a toxic stew of molecules to destroy the abnormal cells. This search-and-destroy function can also target cancer cells for elimination, but tumours often have ways of disarming the immune system, such as by cloaking abnormal proteins or suppressing T-cell function.

CAR-T cells carry synthetic proteins — the chimeric antigen receptors — that span the cell membrane. On the outside is a structure that functions like an antibody, binding to specific molecules on the surface of some cancer cells. Once that has bound, the portion of the protein inside the cell stimulates T-cell activity, hot-wiring it into action. The result is a tiny, revved-up, cancer-fighting machine.

Approved CAR-T therapies target one of two proteins found on immune cells called B cells, and are used to treat certain forms of leukaemia and lymphoma that involve the unchecked proliferation of these cells. The proteins — CD19 and BCMA — are not unique to cancer, meaning that the therapies kill B cells indiscriminately. However, people can live without these cells.

Composite coloured scanning electron micrograph (SEM) of T-cells and prostate cancer cells (pink)
T cells (blue) of the immune system attacking prostate cancer cells (pink).Credit: Steve Gschmeissner/SPL

There is still plenty of room for improvement in CAR-T therapies. Although the effects can be long-lasting — sometimes even curative — cancer eventually returns in most people who have been treated. Solid tumours, such as those found in lung or pancreatic cancers, have so far not responded convincingly to CAR-T cells. The therapy has safety risks and can, in rare instances, be fatal. And it must be custom-made for each recipient, using their own T cells as a starting point, resulting in a relatively slow and expensive manufacturing process.

As yet, there are no simple solutions to any of these problems. “We clearly have a long way to go,” says Mackall. “But we’re now seeing promising signals.”

Some progress is being made against solid tumours. These often contain a heterogeneous mosaic of cells that have different combinations of mutations. This means that a CAR-T therapy directed at a particular mutated protein might work for only one subset of cells. The tight mass of a solid tumour can also be difficult for T cells to penetrate, and researchers have struggled to find suitable targets that won’t wreak havoc in healthy tissues.

Despite this, some clinical trials have shown glimmers of efficacy. Mackall and her colleagues have engineered CAR-T cells to target a molecule called GD2, which is expressed at high levels by some brain and spinal-cord cancers called gliomas. The team gave one intravenous dose of CAR-T therapy to people with gliomas, then administered multiple, lower doses directly into the brain. She and her colleagues reported last year that three of four people treated in this way responded positively1. “These cells just dive right into the brain,” says Mackall. “And the body doesn’t reject them up there — it’s playing in that immune-privileged space.”

Targeting solid tumours could require T-cell therapies that recognize more than one mutated protein or that can target cancer cells expressing higher levels of a given protein than normal cells do. One clinical trial that reported results in November 2022 took this to the extreme: rather than using CARs, the team used CRISPR to engineer natural T-cell receptors (see ‘Targeting T cells’) to recognize mutated proteins found in each participant’s tumour2. The individuals received a mixture of cells targeting different proteins, in the hope that solid tumours would be less likely to develop resistance to a therapy with multiple targets. Tumours stopped growing in 5 of the 16 participants 28 days after treatment. Researchers hope to tweak the protocol, including giving higher doses, to boost effectiveness.

TARGETING T CELLS. Graphic showing how cancer treatments use T cells to kill tumours.
Source: Premier Research; adapted from https://go.nature.com/3WXCRYX

The ability to track and fine-tune T-cell activity is also improving, says immunologist Carl June at the University of Pennsylvania. Through advanced single-cell analyses, researchers can follow the fate of both the engineered cells and the tumours they are designed to kill. They can determine which T cells have become ‘exhausted’ — a dysfunctional state that can come from prolonged stimulation — and which tumour cells are becoming resistant to treatment. They can also see whether the environment surrounding a CAR-T-treated tumour has become riddled with immune-suppressing cells (such as macrophages or regulatory T cells). Overcoming that local immune suppression will be key to harnessing T cells to fight solid tumours, says Yangbing Zhao, chief scientific officer at UTC Therapeutics, a biotechnology company headquartered in Singapore that is developing CAR-T therapies. “No matter how many targets you target, if the tumour is evading the immune response, it won’t work,” he says.

June and his colleagues used a single-cell approach to study resistance to CAR-T therapies that target CD19, and found that CAR-T products that were less able to activate certain helper T cells were associated with the emergence of resistance3. They also used single-cell techniques to learn more about why CAR-T cells directed against a protein called mesothelin, found in pancreatic cancer cells, often fail. Reducing the activity of two genes in CAR-T cells might bolster the therapy4. “We’re going to be able to understand these resistance mechanisms,” says June. “And then with all of these tools like CRISPR, we’re going to engineer around them.”

In addition to editing T cells, CRISPR has been used to find more ways of modifying them. Immunologist Alexander Marson at the Gladstone Institutes in San Francisco, California, and his colleagues used CRISPR to activate or suppress thousands of genes in T cells, and then looked at the effect the changes had on the production of crucial immune-regulating proteins called cytokines5. In another screen using CRISPR, the team found that reducing the activity of a protein called RASA2 enhanced the ability of CAR-T cells to kill their targets6. “We’re learning lessons about the genes that we can turn up and turn down to tune T cells to behave as we want,” says Marson.

Synthetic biologists have also set their sights on T cells, and are engineering sophisticated cellular circuits that could allow greater control over the expression of CARs and other proteins that might increase T-cell activity. In December last year, synthetic biologist Wendell Lim at the University of California, San Francisco, and his colleagues reported7 that they had engineered T cells to express both a CAR and IL-2, an immune-regulating protein. IL-2 can improve T-cell penetration into solid tumours and overcome the immunosuppressive signals that tumours release, but it can be toxic when administered systemically. Letting the T cells produce IL-2 enables local administration of the protein, which could bypass its toxicity to other tissues.Last-resort cancer therapy holds back disease for more than a decade

Other synthetic circuits have been designed to allow precise regulation of CAR expression, by placing it under the control of genetic elements that activate the necessary genes in response to a drug8. So far, however, most of these complicated designs have not yet gone through the safety studies and standardization required for use in people, says Sadelain.

Researchers are learning so many lessons that a big question for the field is now determining which engineered T cells to take forwards into human studies, says oncologist Marcela Maus at Massachusetts General Hospital in Boston. “We can invent and innovate so much in the lab, but there is this funnel of translating that into clinical trials,” she says. “There’s so many things we can do. We have to figure out which are the best things to tweak and test in trials.”

Costly business

Manufacturing CAR-T cells is already wildly complex by pharmaceutical standards. So far, all approved therapies require engineering a person’s own T cells to express the CAR. That adds to the time and thus the cost of producing the therapies: in the United States, a single treatment with CAR-T cells can be about US$500,000, not including the cost of hospitalization and associated treatments.

Creating CAR-T cells that can be given to multiple people — often called off-the-shelf cells — has long been viewed as crucial to lowering the price of the therapy. But early results suggest that there is still work to do, says bioengineer Rahul Purwar at the Indian Institute of Technology Bombay. Although the cells can be edited to reduce the chance that they will themselves be eliminated by the immune system, early trials suggest that they do not survive long after infusion and might still be rejected (see, for example, ref. 9)9. “Off-the-shelf is a great approach,” he says. “It is coming, but right now we are not yet there.”Cancer treatments boosted by immune-cell hacking

The therapy is also rarely available outside wealthy countries. In Brazil, haematologist Renato Luiz Guerino Cunha at Oncoclínicas Group in São Paulo was the first in the country to treat someone with CAR-T therapy in 2019. But progress has been slow, he says: he lacks the capacity to rapidly produce large quantities of cells. “In three years, we treated just six patients,” he says. “We need new technology for the processing.”

Producing a CAR-T cell therapy typically involves using a type of virus called a lentivirus as a vector to shuttle in the synthetic CAR gene. But more research into gene therapies has increased demand for clinical-grade lentiviruses. Researchers now wait months and pay top dollar to complete their experiments; Cunha produces his own but can do so only in tiny quantities. Improvements to CRISPR gene editing could help in this regard.

Despite the challenges, CAR-T therapies continue to expand, with some of the hundreds of clinical trials worldwide exploring entirely new applications. Last year, researchers reported promising results in a small trial of CAR-T therapies to treat a form of the autoimmune disease lupus10. And in a study in mice, researchers reprogrammed T cells without the usual first step of removing them from the body, creating CAR-T cells designed to clear scar tissue from the heart11.

In December, June and his colleagues unveiled a way to streamline cell production. At the American Society of Hematology’s annual meeting in New Orleans, Louisiana, the team announced12 that reducing manufacturing times and engineering CAR-T cells to express a protein called IL-18 boosted their efficacy and allowed researchers to reduce the dose of cells given to people. “Those patients had incredible responses,” says Maus of the clinical trial, “which gives you this really tantalizing hint that if you engineer the T cell better, you can make it even more powerful.”

What time is it on the Moon?

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Satellite navigation systems for lunar settlements will require local atomic clocks. Scientists are working out what time they will keep.

Full Moon captured by NASA's Lunar Reconnaissance Orbiter.

Scientists and space agencies have not yet agreed how to define lunar time.Credit: NASA Goddard

The coming decade will see a resurgence in lunar exploration — including dozens of missions and plans to establish permanent bases on the Moon. The endeavours pose myriad challenges. Among them is a subtle, but fundamental, question that metrologists worldwide are working to answer: what time is it on the Moon?

“We’re just starting to lay this out,” says Cheryl Gramling, an aerospace engineer who leads the position, navigation and timing team at NASA’s Goddard Space Flight Center in Greenbelt, Maryland.The $93-billion plan to put astronauts back on the Moon

The Moon doesn’t currently have an independent time. Each lunar mission uses its own timescale that is linked, through its handlers on Earth, to coordinated universal time, or utc — the standard against which the planet’s clocks are set. But this method is relatively imprecise and spacecraft exploring the Moon don’t synchronize the time with each other. The approach works when the Moon hosts a handful of independent missions, but it will be a problem when there are multiple craft working together. Space agencies will also want to track them using satellite navigation, which relies on precise timing signals.

It’s not obvious what form a universal lunar time would take. Clocks on Earth and the Moon naturally tick at different speeds, because of the differing gravitational fields of the two bodies. Official lunar time could be based on a clock system designed to synchronize with utc, or it could be independent of Earth time.

Representatives of space agencies and academic organizations worldwide met in November 2022 to start drafting recommendations on how to define lunar time at the European Space Research and Technology Centre of the European Space Agency (ESA) in Noordwijk, the Netherlands.

Decisions must be made soon, says Patrizia Tavella, who leads the time department at the International Bureau of Weights and Measures in Sèvres, France. If an official lunar time is not established, space agencies and private companies will come up with their own solutions, she says. “This is why we want to raise an alert now, saying let’s work together to take a common decision.”

Tracking satellites

The most pressing need for lunar time comes from plans to create a dedicated global satellite navigation system (GNSS) for the Moon, similar to how GPS and other satellite navigation networks enable precise location tracking on Earth. Space agencies plan to install this lunar GNSS from around 2030. ESA approved a lunar satellite navigation project called Moonlight at its ministerial council meeting on 22 and 23 November 2022 in Paris, and NASA established a similar project, called Lunar Communications Relay and Navigation Systems, last January.

Until now, Moon missions have pinpointed their locations using radio signals sent to large antennas on Earth at scheduled times. But with dozens of missions planned, “there’s just not enough resources to cover everybody”, says Joel Parker, an engineer who works on lunar navigation at the Goddard Center.

Satnav on the moon: Diagram showing the four satellites orbiting the moon and a spacecraft and comms tower on the surface.
Image credit: NASA

As a first step, from 2024, ESA and NASA will trial deriving positions on the Moon using faint satellite navigation signals from Earth-based craft. Next, the lunar GNSS projects plan to place dedicated satellites around the Moon, each containing their own atomic clock (see ‘Satnav on the Moon’). A receiver, for example on the Moon’s surface, will then triangulate its position using the time it takes for satellite signals to reach it. ESA has planned an initial constellation of four spacecraft that would cover navigation at the lunar south pole, which harbours much of the Moon’s water and is an important target for exploration, says Jörg Hahn, an engineer working on ESA’s Moonlight project.

Moon missions will also need an official lunar time to cooperate and communicate, says Hahn. “All this has to trace to one kind of a time reference, otherwise you have chaos and things do not work together.”

Another open question, says Hahn, is whether astronauts would use universal lunar time everywhere on the Moon. Although lunar time would remain the official timescale, its users might, as on Earth, want to offset it in time zones that link to the Sun’s position in the sky. This is less a question for metrologists and more one of convention. “When somebody really lives there on the Moon, I think it makes sense,” he says.

Characterizing time

Defining lunar time is not simple. Although the definition of the second is the same everywhere, the special theory of relativity dictates that clocks tick slower in stronger gravitational fields. The Moon’s gravitational pull is weaker than Earth’s, meaning that, to an observer on Earth, a lunar clock would run faster than an Earth one. Gramling estimates that a lunar clock would gain about 56 microseconds over 24 hours. Compared with one on Earth, a clock’s speed would also subtly change depending on its position on the lunar surface, because of the Moon’s rotation, says Tavella. “This is a paradise for experts in relativity, because you have to take into account so many things,” she adds.

Defining a lunar standard, with which all clocks are compared, will involve installing at least three master clocks that tick at the Moon’s natural pace, and whose output is combined by an algorithm to generate a more accurate virtual timepiece (see ‘How to build a Moon clock’).

What happens then depends on which option metrologists choose. They might decide to base lunar time on utc. In that case, this virtual lunar time would be synchronized regularly with terrestrial utc. Between the check-ins, the lunar master clocks would keep marking time until the next synchronization. This has the advantage of being simple for users back on Earth to interact with.

How to build a moon clock: Diagram showing three atomic clocks on the moon that could be used to determine lunar time.
Image credit: NASA

The alternative would be to use the synthesized output of the lunar atomic clocks as the Moon’s own independent, continuous time, and to track its relationship to utc. That way, even if the connection with Earth is lost, clocks on the Moon will still agree with each other and allow safe navigation and communications, says Gramling. Establishing an independent time is a model that will also work for the more-distant planets that space agencies are ultimately targeting, such as Mars. Transmitting utc there would be more complicated than to the Moon, she adds.

In this scenario, days on the Moon could even be defined differently from those on Earth, to account for the time from solar noon to solar noon taking an average of 29.5 Earth days. Earth days will always matter to astronauts, given the human need for sleep on a roughly 24-hour cycle. But the definition is something metrologists will need to agree on.NASA’s Orion spacecraft reaches the Moon — in pictures

Metrologists will also need to decide where on the Moon to place the master clocks. As on Earth, the devices’ altitude will affect ticking speed. The clocks could be in lunar orbit or on the surface, says Hahn. “This is what we are discussing right now with our NASA colleagues.”

Space agencies are also considering other necessary standards — such as which maps of the lunar terrain and coordinate systems to use for navigation — through the Interagency Operations Advisory Group, a council of national space agencies and the United Nations International Committee on GNSS. To make various countries’ systems interoperable, reference systems will have to be agreed internationally, says Gramling.

With ESA’s help, NASA is developing a framework called LunaNet, for which it hopes to get international buy-in. LunaNet consists of a set of rules that would enable all lunar satellite navigation, communication and computing systems to form a single network similar to the Internet, regardless of which nation installs them. Setting lunar time is part of a much bigger picture.

“The idea is to produce a Solar System internet,” says Gramling. “And the first part would be at the Moon.”

When Enough is Enough

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When is Enough, Enough?

When is enough, enough?

You might be a little confused about this question, or you might know exactly what I mean, but allow me to explain anyway.

Lately life has been some sort of a rollercoaster and even though I’ve been reading and listening to a lot of personal development, life, and spiritual books and content, it is still a challenge to be dealing with it all when it hits me. And many times it happens when I am at peace, feeling grateful and experience joy in most aspects of my life.

When is Enough, Enough?

It’s almost as if I keep being tested. It’s almost as if I need to understand that I still haven’t learned my lessons and there’s much more for me to take in.

When enough is enough Charlie Chaplin’s Profound Message to Humanity Feeling Afraid: 33 Things You Should Remember When You’re Afraid

It’s almost as if I get too “cocky” in my feel good states and I need to have my feet back on the ground because my balance would be off if I stayed there. Every time it happens I am reminded about what the great Lao Tzu stated so wisely in the Tao Te Ching:

“He who stands on tiptoe
doesn’t stand firm.
He who rushes ahead
doesn’t go far.
He who tries to shine
dims his own light.
He who defines himself
can’t know who he really is.
He who has power over others
can’t empower himself.
He who clings to his work
will create nothing that endures.

If you want to accord with the Tao,
just do your job, then let go.”~ Lao Tzu

When Enough is Enough

There’s nothing wrong with experiencing joy and happiness, bliss and peace, but when experiencing the opposite brings me so much pain, stress, and anxiety, for sure something is not right. Again, not because one shouldn’t experience such beautiful feelings, but because one should experience everything that life brings his way from a place of balance, peace, and discernment. Good or bad, the balance should always be there.

Nothing and no one should have so much power over you that you lose your own peace, balance and inner bliss. You are bigger than any of it, and the moment you realize this, that’s the moment everything changes. Life changes.

It had happened to me so many times to fall in a deep pit of despair and self defeating thoughts, feeling like I will never amount to anything, like my wings were simply cut off and I would have no way to get back up. Yet, every single time I got back up. Every single time I got back up stronger, and wiser.

This year was a challenging one for me and I just feel like I’m still shaking have some leftovers to shake off but I am getting there and that’s because I started saying enough is enough!

When is Enough, Enough? Lacking Motivation? Here's Why Expectations: 5 Life-Altering Ways to Give up Living Your Life According to Other People’s Expectations 8 Ways To Become The Kind Of Person You Would Love To Date 6 Practical Tips to Start a Meaningful Conversation with Someone Jordan Peterson on Removing Toxic Friends from Your Life 12 Stories We Need to Stop Telling Ourselves 19 Life-Changing Lessons to Learn from Lisa Nichols 33 Life-Changing Lessons to Learn from William Blake How to Build Self Respect: 7 Steps to a Healthy Self-image 7 Ways to Stop Comparing Yourself to Others On Liking Yourself Just the Way You Are 5 Reasons Why Self-Love Isn’t Selfish The Importance of Self Love and How to Cultivate it 6 Things You Should Know About Yourself Approval Seeking Behavior: How to Let Go of It You Are Enough 15 Beautiful Ways to Be Fearless Regardless of Your Age

How did this happen?

Well…

For me ENOUGH was enough when I felt like I couldn’t fall any lower and I decided that was it. I had to pick myself up, dust myself off and LIVE again. Not that I had ever stopped, but living in the real sense of the word. Living in Love, Joy, Peace and Freedom.

For me ENOUGH was enough when I felt like there needs to be more to life than the struggles, the lacking, the emptiness and the need to fill that eternal void from my Soul with things of the world.

Looking back a few months, for me ENOUGH was enough when I was sitting on the bathroom floor, crying my eyes and heart out, and I was there because I didn’t want my feelings to “disturb” the people in the house. That was a very low point in my life and nobody should be hiding themselves in their vulnerable moments just because others might not be comfortable with it, or might not know how to deal with it.

“Owning our story can be hard but not nearly as difficult as spending our lives running from it. Embracing our vulnerabilities is risky but not nearly as dangerous as giving up on love and belonging and joy—the experiences that make us the most vulnerable. Only when we are brave enough to explore the darkness will we discover the infinite power of our light.” ~ Brené Brown

It takes lots of courage and strength to show yourself in your most vulnerable moments, and if you have to hide yourself during these moments, then who are you?

For me ENOUGH was enough when I decided that what other people do, say to me and about me, is not a reflection of who I am, but a reflection of who they themselves are. You’ll never be able to make everyone happy and you shouldn’t even have to. We’re all so beautifully different and once we accept one another and stop trying to fit everyone in a mould, that’s when life really gets exciting.

For me ENOUGH was enough when I decided to be free. Free from what other people expect or project onto me, free from what I “should” have already done at my age and why I didn’t do it. Free from the past and the people in it and free from the ideas I had created in my mind about how my life should have been by now.

When is Enough, Enough? How to No Longer Allow Your Expectations Get in the Way of Your Happiness

Sometimes people ask me more personal questions and lately I’ve just been thinking I shouldn’t have to explain whether I’m in a relationship, or why I’m not married, why I don’t have a family yet, and I can go on forever.

My life is mine to live and as long as my choices do not harm anyone, I shouldn’t have to justify any of it to anyone, right?

I do my best to live a life that’s in alignment with my values, in alignment with Love, Discernment, Kindness, and I know I have been challenged and tested this year, but I refuse to give up. I refuse to be bitter instead of better. So I do better with what I have learned from life and do it in such a way that it improves not only my life, but also the lives of those around me.

Here’s to that!

From where I stand right now, I cannot say this journey to living a better life will be smooth, however, what I do know is that no matter what is coming my way, sooner or later, I will be able to get through it. Any life challenge is a life lessons, as long as we are willing to learn and I am.

Are you?

Closed-loop technology could benefit people with type 2 diabetes

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New research shows that closed-loop technology, or an artificial pancreas, holds huge promise for people living with type 2 diabetes. The technology doubled the amount of time people spent with their blood sugars in the target range and halved the time they spent with high blood sugar levels, compared to using insulin injections.

The results from a world-first trial testing closed-loop technology for the management of type 2 diabetes have been announced by scientists at the University of Cambridge.

Closed-loop systems continuously monitors blood sugars levels. An algorithm calculates the amount of insulin required to keep blood sugars in target range, and then automatically delivers this through an insulin pump. 

Most research to date has focused on the benefits of the cutting-edge technology for people with type 1 diabetes. And thanks to decades of clinical trials and a recent NHS pilot roll out of the tech, draft guidance has now been released that could see hybrid closed-loop technology recommended for thousands of people living with type 1.

Many people with type 2 diabetes also need to take insulin to manage their condition, but before technology like this can be made available to people with type 2, we need research to understand if it would be effective and safe.

Unlike the hybrid closed-loops systems that are approved for people with type 1 diabetes, researchers are testing a fully closed-loop system to help manage type 2. The differences between these systems are:

  • With hybrid closed-loop systems, people with type 1 diabetes need to tell their device what they are about to eat to receive their mealtime insulin dose.
  • A fully closed-loop system works to control blood sugar levels entirely automatically. This is possible for people with type 2 diabetes because they’re still producing some of their own insulin, which gives a helping hand to the insulin administered by the device.  

With our funding, our scientists previously showed that fully closed-loop technology could transform care for people with type 2 diabetes during hospital stays. Now, researchers at the University of Cambridge have studied the system for the first time in people with type 2 diabetes while they used it at home.

Closing in on closed-loop technology

The Cambridge trial involved 26 people living with type 2 diabetes who use insulin. They tested the fully closed-loop system for eight weeks and spent eight weeks on their standard treatment of multiple daily insulin injections and finger-prick tests. The researchers compared blood sugar levels between closed-loop vs standard insulin treatment.  

The results of the trial suggest that the technology is a safe and effective way to help people with type 2 diabetes manage their blood sugar levels. The research team found:

  • People spent on average two-thirds (66%) of their time within the target blood sugar range when using the closed-loop technology – double that while using insulin injections (32%)
  • People spent one-third (33%) of their time with high blood sugar levels (above 10mmol/L) – this was doubled to 67% when using insulin injections
  • People had lower average long-term blood sugar (HbA1c) levels of 7.3% after using the closed-loop technology, compared to 8.7% after standard insulin treatment
  • No one experienced dangerously low blood sugar levels during the study with either treatment.

The team also asked participants about the pros and cons of the tech and the impact it had on their daily life. These results revealed:

  • Nine out of 10 of those taking part said it meant they could spend less time self-managing their diabetes
  • Stopping the need for injections or finger-pricks and having greater confidence in managing blood sugar levels were highlighted as key benefits 
  • Downsides included increased anxiety about the risk of hypos (low blood sugar) and annoyances about the practicality of wearing the devices.

First steps to wider access

We’ve long supported research to develop the artificial pancreas and are committed to making sure this technology can benefit as many people with diabetes as possible in the future.

It’s really encouraging to see the research evidence build, which will be required in order to offer this type of technology to some people with type 2 in the future. Before that can happen, we’ll need larger and longer-term studies to confirm the potential benefits and understand the practicalities.

Most of the people who took part in this small trial were White, and everyone lived in the same area – so the study isn’t representative of the wider population of people living with type 2 diabetes.

The group taking part also had an average HbA1c level of 9% at the start of the study, so we don’t know if the tech would be as beneficial for people with type 2 and a lower HbA1c.

It’s also possible that some the benefits seen could be down to participants having access to continuous glucose monitoring for the first time (all were testing with finger pricks previously). So there’s more we need to untangle about which type of diabetes technology could be most helpful and cost-effective for people with type 2.

The research team at the University of Cambridge team now plan to carry out follow-on bigger studies to get more answers.

Targeting DNA damage response pathways in cancer

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Abstract

Cells have evolved a complex network of biochemical pathways, collectively known as the DNA damage response (DDR), to prevent detrimental mutations from being passed on to their progeny. The DDR coordinates DNA repair with cell-cycle checkpoint activation and other global cellular responses. Genes encoding DDR factors are frequently mutated in cancer, causing genomic instability, an intrinsic feature of many tumours that underlies their ability to grow, metastasize and respond to treatments that inflict DNA damage (such as radiotherapy). One instance where we have greater insight into how genetic DDR abrogation impacts on therapy responses is in tumours with mutated BRCA1 or BRCA2. Due to compromised homologous recombination DNA repair, these tumours rely on alternative repair mechanisms and are susceptible to chemical inhibitors of poly(ADP-ribose) polymerase (PARP), which specifically kill homologous recombination-deficient cancer cells, and have become a paradigm for targeted cancer therapy. It is now clear that many other synthetic-lethal relationships exist between DDR genes. Crucially, some of these interactions could be exploited in the clinic to target tumours that become resistant to PARP inhibition. In this Review, we discuss state-of-the-art strategies for DDR inactivation using small-molecule inhibitors and highlight those compounds currently being evaluated in the clinic.

Source: Nature