Pineapple Extract Enhances Chemo Effectiveness on Mesothelioma Cells

Jan 10, 2014   Tim Povtak

A future cancer treatment may have emerged with the recent discovery that bromelain, a pineapple extract, can improve the effectiveness of cisplatin chemotherapy on peritoneal mesothelioma tumor cells.

Bromelain is an enzyme found in the stem and the juice of a pineapple. It has been part of the natural, alternative medicine culture for many years, dating back centuries in Central and South America.

The pineapple enzyme may be close to moving into the realm of more conventional medicine in a very significant way, thanks to recent, groundbreaking research at the University of New South Wales in Australia.

"This is a treatment combination that is really dramatic, and likely to alter the efficacy of chemotherapy in many types of cancer," Professor David Morris, UNSW Department of Surgery, told Asbestos.com. "It has been exciting to see."

Searching for Answers

The lack of effective treatment options for all types of mesothelioma continues to frustrate medical professionals trying to treat the rare, but aggressive cancer that is caused byexposure to asbestos fibers.

Standard treatment today includes a chemotherapy regimen that typically involves cisplatin or pemetrexed, although it comes with difficult side effects and works inconsistently. The majority of mesothelioma patients live less than 18 months after diagnosis, even with the best care.

Bromelain might change that prognosis in the future.

Although previous studies have shown that bromelain can suppress breast and pancreatic cancer cells, this was the first one published on its ability to enhance cisplatin therapy with mesothelioma cells.

Morris believes the laboratory findings were so significant that they quickly will move into theclinical trial phase. Animal safety testing already has been done.

"If it's not within the next year, I'll be very disappointed," he said.

He also expressed the desire to study the effect on pleural mesothelioma - the more prevalent, more difficult type to treat. Pleural involves the thin lining around the lungs.Peritoneal involves the abdominal cavity.

"Whether we can get the same results in the chest, for pleural mesothelioma, is clearly one of the really big unanswered questions at the moment," Morris said. "It's something we plan to pursue."

Bromelain Combination Should Prevent Spread of Cancer

The research focused on the ability of the bromelain enzyme to break down the protein MUC-1 in mesothelioma cell lines through a chemical decomposition process. The MUC-1 protein is what helps the cancer cells metastasize and allows it to resist the toxicity of chemotherapy.

The cell lines were treated with various concentrations of bromelain with cisplatin and assessed after both four and 72 hours. Bromelain also was used with 5-fluorouracil (5-FU), another treatment drug. The Bromelain did little to help the 5-FU, but it significantly increased the toxicity of the cisplatin on the tumor cells.

Although it still lacks definitive, scientific evidence, bromelain has been used for years as a natural anti-inflammatory. Researchers recently have been uncovering several cancer-killing mechanisms within the enzyme, and clinical trials in Europe involving breast and colon cancer patients have met mixed results.

The website for the Memorial Sloan-Kettering Cancer Center in New York has information on bromelain within its Integrative Medicine section. Among the "purported uses," are treating arthritis, treating burns of the skin, preventing and treating cancer, treating circulatory disorders and reducing swelling and edema.

Under each purported use is a disclaimer stating either that clinical trials have not been done, or that there has not been official confirmation of its worthiness.

Bromelain currently is regulated by the FDA as a dietary supplement. It may be on the verge of becoming significantly more important.

"Quite remarkably, we just don't have good chemotherapy drugs now for mesothelioma," Morris said. "It is likely this will at least get us a second-line drug. I'll be disappointed if this doesn't turn out much better than that."

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Dietary supplements: do any work for atopic dermatitis?

Eczema is a skin condition characterised by an itchy, red rash, which affects 5% to 20% of people worldwide. There is no cure, but many treatments can help improve the skin's condition, making life easier. In those for whom these treatments do not work well or who fear their long-term effects, there is often a belief that either something in their diet, or something missing in their diet, is making their eczema worse.

This review looked at the following dietary supplements (products which add ingredients to a diet): fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine (vitamin B6), sea buckthorn oil, hempseed oil, and sunflower oil. 

Three commonly used dietary supplements (evening primrose oil, borage oil, and probiotics) are currently the subject of other Cochrane reviews (Boehm 2003; Boyle 2008).

We looked for trials comparing supplements with placebo (dummy). We included 11 randomised controlled trials (596 participants) when it was clear that the children or adults taking part had atopic eczema. In reviewing the trials, the main outcomes we looked for were evidence of improvement in the symptoms of eczema, such as itching or loss of sleep, in the short-term (i.e. six weeks). In the longer term, we wanted to see evidence of a reduced need for treatment for the eczema or a reduction in the number of flares. We also looked for evidence of any general improvement in the eczema and in individual symptoms. 

Overall, we found no convincing evidence that taking supplements improved the eczema of those involved. In general, studies were small with low numbers of participants and of poor quality in terms of the way they were run. Two trials of fish oil did find slight improvement for the participants in terms of the degree of itchiness and quality of life. However, these trials had small numbers, which means they had little chance of finding real differences if they did exist. That is why larger trials are needed before any recommendations can be made. We found no evidence of adverse (harmful) effects in those who took part in the trials. People sometimes think that supplements can at least do no harm; however, high doses of vitamin D, for example, can cause serious medical problems, and the safety of dietary supplements should not be assumed. The cost of supplements can also mount up. 

Background: Many people with atopic eczema are reluctant to use the most commonly recommended treatments because they fear the long-term health effects. As a result, many turn to dietary supplements as a possible treatment approach, often with the belief that some essential ingredient is 'missing' in their diet. Various supplements have been proposed, but it is unclear whether any of these interventions are effective.

Objectives: To evaluate dietary supplements for treating established atopic eczema/dermatitis.

Evening primrose oil, borage oil, and probiotics are covered in other Cochrane reviews.

Search methods: We searched the following databases up to July 2010: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), PsycINFO (from 1806), AMED (from 1985), LILACS (from 1982), ISI Web of Science, GREAT (Global Resource of EczemA Trials) database, and reference lists of articles. We searched ongoing trials registers up to April 2011.

Selection criteria: Randomised controlled trials (RCTs) of dietary supplements for the treatment of those with established atopic eczema/dermatitis.

Data collection and analysis: Two authors independently screened the titles and abstracts, read the full text of the publications, extracted data, and assessed the risk of bias.

Main results: We included 11 studies with a total of 596 participants. Two studies assessed fish oil versus olive oil or corn oil placebo. The following were all looked at in single studies: oral zinc sulphate compared to placebo, selenium versus selenium plus vitamin E versus placebo, vitamin D versus placebo, vitamin D versus vitamin E versus vitamins D plus vitamin E together versus placebo, pyridoxine versus placebo, sea buckthorn seed oil versus sea buckthorn pulp oil versus placebo, hempseed oil versus placebo, sunflower oil (linoleic acid) versus fish oil versus placebo, and DHA versus control (saturated fatty acids of the same energy value). Two small studies on fish oil suggest a possible modest benefit, but many outcomes were explored. A convincingly positive result from a much larger study with a publicly-registered protocol is needed before clinical practice can be influenced.

Authors' conclusions: There is no convincing evidence of the benefit of dietary supplements in eczema, and they cannot be recommended for the public or for clinical practice at present. Whilst some may argue that at least supplements do not do any harm, high doses of vitamin D may give rise to serious medical problems, and the cost of long-term supplements may also mount up.

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Self-help for panic disorder or social phobia

Anxiety disorders are very common and difficult to deal with. The term “anxiety disorders” covers many conditions, including panic and phobias.

One option for treating anxiety disorders is self-help based on therapy principles. Using a book or a website to help, a person tackles the kinds of exercises that would be used in therapy, but they do it on their own, perhaps with some email or phone support from a therapist.

Researchers from Cardiff University in Wales were able to find and analyze 31 trials testing the effects of this kind of self-help. The best-studied conditions were panic disorder and social phobia. People with social phobia often experience extreme anxiety when they encounter or face other people.

The researchers found that websites, books, and other materials based on cognitive-behavioral therapy (CBT) could help some people. You can read a quick overview of CBT here or in more depth here.

The Cardiff researchers’ summary of their review is here.

Citation: Lewis C, Pearce J, Bisson JI. Efficacy, cost-effectiveness and acceptability of self-help interventions for anxiety disorders: systematic review. British Journal of Psychiatry 2012; 200(1): 15-21. PMID 22215865

If you would like to read more background information about issues related to computerized CBT for anxiety, a review was published by England’s National Institute for Health Research (NIHR) in 2006. It is summarized in detail here, with full text accessible here.

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Physiotherapy and Parkinson's Disease

In spite of various medical and surgical treatments for Parkinson's disease (PD), patients gradually develop significant physical problems. Physiotherapists aim to enable people with PD to maintain their maximum level of mobility, activity, and independence by monitoring their condition and targeting appropriate treatment. A range of approaches to movement rehabilitation are used, which aim to enhance quality of life by maximising physical ability and minimising problems related to Parkinson's over the whole course of the disease.

Only randomised controlled trials were included in this review. In these studies,a group of participants were given physiotherapy intervention and were compared with another group of participants, who did not receive physiotherapy. Participants were assigned to a group in random fashion so a fair test was established. Thirty-nine randomised trials involving 1827 participants were identified as suitable for this review. The quality of the trials was not high because in many, methods were not reported adequately and blinding was not feasible. These trials assessed various physiotherapy interventions, so the trials were grouped according to the type of intervention being used (i.e. general physiotherapy, exercise, treadmill training, cueing, dance, or martial arts).

Improvement in all walking outcomes (except the 10- or 20-metre walk test) was noted with physiotherapy intervention. However, these improvements were significant only for walking speed, walking endurance, and freezing of gait. Mobility and balance also improved with a physiotherapy intervention, with significant improvements reported in one test of mobility (the Timed Up & Go test, which times how long it takes a person to get up from a chair, walk a certain distance, then walk back to the chair and sit down) and in two tests of balance (one assessing how far a person can reach before he or she loses balance (Functional Reach Test) and another assessing multiple aspects of balance (Berg Balance Scale)). Clinician-rated disability, using the Unified Parkinson’s Disease Rating Scale (UPDRS), was also improved with physiotherapy intervention. No difference was observed between the two groups in falls or patient-rated quality of life. One study reported that adverse events were rare; no other studies reported data on this outcome. When the different physiotherapy interventions were compared, no evidence suggested that treatment effect differed across the physiotherapy interventions for any of the outcomes assessed.

This review provides evidence of the short-term benefit of physiotherapy for the treatment of PD. Although most observed differences were small, improvements in walking speed, balance with the Berg Balance Scale, and clinician-rated disability using the UPDRS were of a size that patients may consider them to be important. These benefits should be interpreted with caution because of the quality of the included trials, and the lack of common assessment of treatment effects. This affected the quantity of data that we could use for analysis.

Background: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. Physiotherapy aims to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety, and well-being, thereby enhancing quality of life.

Objectives: To assess the effectiveness of physiotherapy intervention compared with no intervention in patients with PD.

Search methods: We identified relevant trials by conducting electronic searches of numerous literature databases (e.g. MEDLINE, EMBASE) and trial registers, and by handsearching major journals, abstract books, conference proceedings, and reference lists of retrieved publications. The literature search included trials published up to the end of January 2012.

Selection criteria: Randomised controlled trials of physiotherapy intervention versus no physiotherapy intervention in patients with PD.

Data collection and analysis: Two review authors independently extracted data from each article. We used standard meta-analysis methods to assess the effectiveness of physiotherapy intervention compared with no physiotherapy intervention. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance, and martial arts. We used tests for heterogeneity to assess for differences in treatment effect across these different physiotherapy interventions.

Main results: We identified 39 trials with 1827 participants. We considered the trials to be at a mixed risk of bias as the result of unreported allocation concealment and probable detection bias. Compared with no intervention, physiotherapy significantly improved the gait outcomes of speed (mean difference 0.04 m/s, 95% confidence interval (CI) 0.02 to 0.06, P = 0.0002); two- or six-minute walk test (13.37 m, 95% CI 0.55 to 26.20, P = 0.04) and Freezing of Gait questionnaire (-1.41, 95% CI -2.63 to -0.19, P = 0.02); functional mobility and balance outcomes of Timed Up & Go test (-0.63 s, 95% CI -1.05 to -0.21, P = 0.003), Functional Reach Test (2.16 cm, 95% CI 0.89 to 3.43, P = 0.0008), and Berg Balance Scale (3.71 points, 95% CI 2.30 to 5.11, P < 0.00001); and clinician-rated disability using the Unified Parkinson’s Disease Rating Scale (UPDRS) (total -6.15 points, 95% CI-8.57 to -3.73, P < 0.00001; activities of daily living: -1.36, 95% CI -2.41 to -0.30, P = 0.01; and motor: -5.01, 95% CI -6.30 to -3.72, P < 0.00001). No difference between arms was noted in falls (Falls Efficacy Scale: -1.91 points, 95% CI -4.76 to 0.94, P = 0.19) or patient-rated quality of life (PDQ-39 Summary Index: -0.38 points, 95% CI -2.58 to 1.81, P = 0.73). One study reported that adverse events were rare; no other studies reported data on this outcome. Indirect comparisons of the different physiotherapy interventions revealed no evidence that the treatment effect differed across physiotherapy interventions for any of the outcomes assessed.

Authors' conclusions: Benefit for physiotherapy was found in most outcomes over the short term (i.e. < 3 months) but was significant only for speed, two- or six-minute walk test, Freezing of Gait questionnaire, Timed Up & Go, Functional Reach Test, Berg Balance Scale, and clinician-rated UPDRS. Most of the observed differences between treatments were small. However, for some outcomes (e.g. speed, Berg Balance Scale, UPDRS), the differences observed were at, or approaching, what are considered minimal clinically important changes. These benefits should be interpreted with caution because the quality of most of the included trials was not high. Variation in measurements of outcome between studies meant that our analyses include a small proportion of the participants recruited.

This review illustrates that a wide range of approaches are employed by physiotherapists to treat patients with PD. However, no evidence of differences in treatment effect was noted between the different types of physiotherapy interventions being used, although this was based on indirect comparisons. A consensus menu of 'best practice' physiotherapy is needed, as are large, well-designed randomised controlled trials undertaken to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.

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Milnacipran and fibromyalgia symptoms

The aim of this review was to assess how effective milnacipran is for treating chronic neuropathic pain or fibromyalgia. We identified no studies using milnacipran in neuropathic pain, but five studies in fibromyalgia satisfied the inclusion criteria. Fibromyalgia is a complex pain syndrome, defined as widespread pain for longer than three months; the original diagnostic criteria involved pain on palpation at 11 or more of a number of specified tender points (Wolfe 1990), with later criteria including both widespread pain and symptom severity (Wolfe 2010). The studies included over 4000 participants treated with milnacipran 100 mg or 200 mg, or placebo, for eight to 24 weeks at the target dose. Overall study quality was good, although the method of analysis for our primary outcomes could overestimate treatment effect.

Milnacipran at either dose provided moderate pain relief (at least 30% reduction in pain intensity) to 10% more participants than did placebo. This relatively modest effect may be clinically important in this difficult to treat condition. Adverse events were reported by the majority of participants in all groups, but were more common with milnacipran than placebo, with nausea and constipation showing the greatest differences. Serious adverse events were uncommon (less than 2%) and did not differ between treatment groups. Withdrawals due to adverse events were also more common with milnacipran than placebo, and were more common with 200 mg than 100 mg, while withdrawals due to lack of efficacy were less common with milnacipran, with no difference between doses.

Milnacipran has shown modest effects in a minority of participants with fibromyalgia, and several technical issues indicate that even this modest effect may overstate effectiveness in clinical practice The drug may be a useful option if first-line treatments fail.

Background: Milnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) that is sometimes used to treat chronic neuropathic pain and fibromyalgia.

Objectives: To evaluate the analgesic efficacy and adverse effects of milnacipran in the management of chronic neuropathic pain or fibromyalgia.

Search methods: We searched CENTRAL, MEDLINE, and EMBASE to 4th of January 2012, together with reference lists of retrieved papers and reviews.

Selection criteria: We included randomised, double-blind studies of eight weeks duration or longer, comparing milnacipran with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.

Data collection and analysis: We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently.

Main results: Five studies (4138 participants) were included, all of which were placebo-controlled, involved participants with fibromyalgia, and used titration to a target dose of 100 mg or 200 mg milnacipran. There were no other active comparators or studies in other neuropathic pain conditions. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.

Both doses of milnacipran provided moderate levels of pain relief to about 40% of those treated, compared to 30% with placebo, giving a number needed to treat of 8 to 10. Adverse events were common in both milnacipran (87%) and placebo (78%) groups, but serious adverse events (< 2%) did not differ between groups. Nausea and constipation were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome of 7 and 13 respectively, compared with placebo).

Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg than 100 mg (NNH of 23 and 8.8 respectively, compared with placebo). This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg, and 7.0 for 200 mg). Withdrawals due to lack of efficacy were more common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome of 45 and 41 respectively).

Authors' conclusions: The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Milnacipran is associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose. There were no data for the use of milnacipran for other chronic neuropathic pain conditions.

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Epilepsy: Ketogenic and Atkins diets

When the body gets its energy mostly from fats instead of carbohydrates, it produces substances called ketones. Although it is not clear why, a ketogene-producing diet (“ketogenic”) can reduce the number of seizures in some people with epilepsy.

The Atkins diet is a modified ketogenic diet. With Atkins, people eat twice as much fat as carbs. A full ketogenic diet is more severe: the ratio is four times as much fat. That is very hard to stick with over time. Close supervision is needed, because radical diets can be harmful. Stomach and gut problems are common, and there may be a chance of long-term adverse cardiovascular effects.

According to a review from the Cochrane Collaboration, there have now been some trials of ketogenic and modified ketogenic diets in children and young people with epilepsy. In all the trials, nearly 40% of the children and young people in the diet group had half or fewer seizures than they had before—including in the less radical diet trials.

Adverse effects like constipation were common (around 30%), but the less radical diets were easier to tolerate. The researchers found that only about 10% were still on the diets after a few years.

Research into modified diets for epilepsy is continuing.

You can read the Cochrane review summary here.

The full Cochrane review is on The Cochrane Library here.

Citation: Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD001903. DOI: 10.1002/14651858.CD001903.pub2. Link to Cochrane Library

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Quitting smoking

When people stop smoking they experience cravings to smoke and unpleasant mood changes. Nicotine receptor partial agonists aim to reduce withdrawal symptoms and smoking satisfaction. Two recent trials of cytisine (937 people) confirm that it can be an effective and affordable treatment for smoking cessation. Quit rates were low, however, at around 9% in the treatment groups. The rate might be boosted in future studies by longer treatment and more intensive or extended counselling.

A single trial of dianicline did not detect any benefit over placebo in helping smokers to quit. This drug is no longer being developed.

We found 15 randomized controlled trials of varenicline compared with placebo. Three of these trials also included a direct comparison with bupropion. We also found one trial comparing varenicline plus counselling with counselling alone. One other trial tested varenicline against placebo, as maintenance therapy for those who had recently quit with varenicline. Two further trials compared varenicline with nicotine patches. One trial gave varenicline to all participants, but varied the delivery of behavioural support. This trial is not included in the analyses, but contributes to the data on safety and tolerability.

From these data (14 trials, 6166 people), varenicline at standard dose increased the chances of quitting more than two-fold compared with placebo. Low-dose varenicline (four trials, 1272 people) roughly doubled the chances of quitting, and reduced the number and severity of side effects. The number of people stopping smoking with varenicline was higher than with bupropion (three trials, 1622 people). The two trials with nicotine patches (778 people) did not show a clear benefit of varenicline over the patches. The main side effect of varenicline was nausea, but this was mostly at mild or moderate levels and usually subsided over time. There may be a one-third increase in the chance of severe side effects among people using varenicline, but this finding needs to be tested further. After the licensing phase, there were concerns that varenicline may be linked with an increase in depressed mood, agitation, or suicidal thinking and behaviour in some smokers. There are also concerns that it may slightly increase heart and circulatory problems in people already at increased risk of these illnesses. Surveillance studies and further analyses of the trial data have not found strong support for either of these associations so far, but we cannot rule out the possibility of such links.

Background: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist).

Objectives: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation.

Search methods: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in December 2011. We also searched online clinical trials registers.

Selection criteria: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment.

Data collection and analysis: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up.

The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model.

Main results: Two recent cytisine trials (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled RR of 3.98 (95% confidence interval (CI) 2.01 to 7.87).

One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75).

Fifteen trials compared varenicline with placebo for smoking cessation; three of these also included a bupropion treatment arm. We also found one open-label trial comparing varenicline plus counselling with counselling alone. We found one relapse prevention trial, comparing varenicline with placebo, and two open-label trials comparing varenicline with nicotine replacement therapy (NRT). We also include one trial in which all the participants were given varenicline, but received behavioural support either online or by phone calls, or by both methods. This trial is not included in the analyses, but contributes to the data on safety and tolerability. The included studies covered 12,223 participants, 8100 of whom used varenicline.

The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.27 (95% CI 2.02 to 2.55; 14 trials, 6166 people, excluding one trial evaluating long term safety). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4 trials, 1272 people). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 1.35; 2 trials, 778 people). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. A meta-analysis of reported serious adverse events occurring during or after active treatment and not necessarily considered attributable to treatment suggests there may be a one-third increase in the chance of severe adverse effects among people using varenicline (RR 1.36; 95% CI 1.04 to 1.79; 17 trials, 7725 people), but this finding needs to be tested further. Post-marketing safety data have raised questions about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline was amended in 2008, and the manufacturers produced a Medication Guide. Thus far, surveillance reports and secondary analyses of trial data are inconclusive, but the possibility of a link between varenicline and serious psychiatric or cardiovascular events cannot be ruled out.

Authors' conclusions: Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion. Two open-label trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence intervals did not rule out equivalence. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including serious psychiatric or cardiovascular events, cannot be ruled out.

Future trials of cytisine may test extended regimens and more intensive behavioural support. There is a need for further trials of the efficacy of varenicline treatment extended beyond 12 weeks.

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Planned change in bacterial strain-level information management

Please be aware that there is an upcoming change (January 2014) in how NCBI manages organism strain information. Due to significant increases in the volume of strain-specific sequencing, we are changing our management of strain information.

Next generation sequencing has already changed the way microbial genomes are being used. The scope of microbial sequencing projects has shifted from a single isolate representing an organism to multi-isolate and multi-species projects representing microbial communities. Consequently, in the first nine months of 2013 the sequences of more than 6000 prokaryotic genomes were released by INSDC (DDBJ/ENA/GenBank).

NCBI is introducing several changes in prokaryotic genomes and related resources such as Assembly, BioProject, BioSample, and Taxonomy that will affect your submissions, data downloads, analysis tools, and parsers.

Taxonomy

Assigning strain-level TaxID will be discontinued in January 2014 because curation of strain-level TaxIDs will not remain possible under such growth. However, the thousands of existing strain-level TaxIDs will remain, and we will continue to add informal strain-specific names for genomes from specimens that have not yet been identified to the species level, e.g. “Rhizobium sp. CCGE 510” and “Micromonas sp. RCC299”. The strain information will continue to be collected and displayed.

BioSample

Submitters of genome sequences will be required to register sample meta-data in the BioSample database for each organism that they are sequencing. The BioSample submission will include the strain information and other metadata, such as culture collection and isolation information, as appropriate. The BioSample accession will be a link on the GenBank records, and the GenBank records themselves will display the strain in the source information.

BioProject

Submitters of genome sequences are already required to register meta-data about the research project in the BioProject database. We no longer require a one-to-one relationship between a BioProject accession and a genome. Instead, a research effort examining multiple strains of a species or multiple species of drug-resistant bacteria, for example, could be registered as a single BioProject.

Assembly

Each genome assembly is loaded to the Assembly database and assigned an Assembly accession. The Assembly accession is specific for a particular genome submission.

A BioProject ID or accession cannot be used to define a single genome, since many may belong to a multi-isolate or multi-species project. Furthermore, a TaxID can no longer reliably define an individual genome since unique TaxIDs will not be assigned for individual strains and isolates. The collection of DNA sequences of an individual sample (isolate) will be represented by a BioSample accession and if raw sequence reads are assembled and submitted to GenBank they will get a unique Assembly accession. The Assembly accession is specific for a particular genome submission. For example, sequence data generated from a single sample (with a BioSample accession) could be assembled with two different algorithms and so have two sets of GenBank accessions, each with its own Assembly accession.

For example, BioProject PRJNA203445 is a multi-species project with multiple strains and isolates of different food pathogens. Each isolate has its own BioSample accession and each assembled genome has its own Assembly accession. This BioProject includes an isolate of Listeria monocytogenes (TaxID 1639, strain R2-502) which was registered as BioSample SAMN02203126, and its genome is represented in GenBank records CP006595-CP006596, which are tracked as a group in the Assembly database under accession GCA_000438585.

Genome text reports on the FTP site have been modified to include the BioSample and Assembly accessions. These two columns were added at the end of the tables to minimize problems for existing parsers. Initially, not all assemblies will have a BioSample accession because we are still in the process of back-filling BioSamples for genomes.

These changes will occur in January 2014. We will be releasing more information as the date approaches.

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BLAST+ 2.2.29 now available

Stand-alone BLAST version 2.2.29+ is now available for download from the FTP site. BLAST 2.2.29+ provides a number of important improvements and bug fixes. Some improvements include improved blastn batch query performance, source releases build optimized multi-thread binaries by default, and improved multithreading by better dividing the BLAST database among threads. The BLAST Release notes lists more upgrades and fixes.

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Sequence Viewer has been updated

NCBI Sequence Viewer provides a graphical view of sequences and color-coded annotations on regions of sequence stored in the Nucleotide and Protein databases. Sequence Viewer has recently been updated and now has better loading and management of uploaded custom tracks, improved naming of downloaded files including sequence ranges and file extensions, and easier embedding in external Web sites.

A full list of new features, improvements and fixes is available at: http://www.ncbi.nlm.nih.gov/tools/sviewer/release-notes/

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SRA milestone: Over 2 petabases of sequence data

The Short Read Archive (SRA) now contains more than 2 petabases of high-throughput sequence data. One petabase of data is open access, while the rest are sequences from 40,000 individuals who have participated in human clinical studies catalogued in dbGaP.

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NCBI Insights blog: A Librarian's Guide to NCBI - an intensive training course for medical librarians to be offered April 2014

The NCBI in partnership with the National Library of Medicine Training Center (NTC) will offer the Librarian’s Guide to NCBI course on the NIH campus in April 2014. This will be the second presentation of the course; it was previously offered in the spring of 2013 (NCBI Insights April 11 and May 6, 2013). After the course, we will post lecture slides and hands-on practical exercises on the education area of the NCBI FTP site and video tutorials of the course lectures will be available on the NCBI YouTube channel. Materials from the 2013 course are available, as well as lecture videos for the expression module. More information, including prerequisites, is available in the newest NCBI Insights blog post.

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VAST+ released: Find similar 3D structures for macromolecular complexes

VAST+ is a new tool designed to identify macromolecules that have similar 3-dimensional structures with an emphasis on finding similar macromolecular complexes. The similarities are calculated using purely geometric criteria without regard to sequence similarity, and therefore can identify distant homologs.

This new tool is built upon the original Vector Alignment Search Tool (VAST) and expands the capabilities of that program by taking into account the biological unit ("biounit") of each structure, not just individual protein chains or their substructures.

A recent publication provides detailed information about the VAST+ algorithm. In addition, the extensive VAST+ help document includes a comparison of original VAST and VAST+, as well as examples of how can this tool can be used to learn more about proteins.

Please note that in order to view the 3D superpositions of similar biological units, you must install the most recent version of the NCBI molecular viewing software, Cn3D 4.3.1.

Figure. VAST+ search results for Thermotoga maritima Glutamate Dehydrogenase (PDB ID 1B26) with detailed view of a match to 1GTM.

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PMCID - PMID - Manuscript ID - DOI Converter Upgraded

We have upgraded the PMCID - PMID - Manuscript ID - DOI Converter. The updated ID Converter API allows you to convert IDs for publications referenced in PubMed and PMC.

The ID Converter tool allows you to convert IDs for publications referenced in PubMed and PMC. You can also cross-reference Open Access NIH Manuscript Submission IDs (NIHMS) and Digital Object Identifiers (DOIs) often used by publishers.  For example, these identifiers refer to the same publication:

PMCID: PMC3702208

PMID: 24288678

NIHMS: NIHMS518180

DOI: 10.1007/s00213-013-3057-1

This tool uses an underlying web service, which is also publicly available for those needing programmatic access to this data.  For more information, see the ID Converter API documentation.

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New SNP data available for several organisms!

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New SNP data (build 139) is now available on the web and in FTP files for several organisms, including gorilla, horse, dog, sheep, rabbit, opossum, platypus, wild turkey, zebra finch, tomato, grape and aspergillus.

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Update on PubMed Commons' comments in the early pilot phase

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AppId is over the quota

PubMed Commons is a new system that enables researchers to share their opinions about scientific publications indexed in the PubMed database. Participation in PubMed Commons requires users with My NCBI accounts to join before they can view or add comments.

As of November 1, 2013, there are about 1,000 people signed up in the Commons and in just four days of public access the amount of comments on PubMed records doubled to over 200.

Approximately a third of the first ~200 comments included critique or pointed to other studies or reviews with the potential to change people’s interpretations or conclusions. Some authors posted corrections or changed their own conclusions in the light of others’ subsequent work. Authors also used PubMed Commons to update people on their work – including links to databases that have moved, providing contextual information and backstories as well as new, relevant work.

Many PubMed Commons participants took the opportunity to add links to relevant papers and data, sometimes in the non-PubMed academic literature or data repositories – including complete datasets, data re-analyses, blog posts and full text pre-prints of the article.

Around half of the comments were principally discussion, developing lines of thoughts and raising or asking questions and there has already been some interesting back and forth between PubMed Commons participants interested in an issue and authors of the PubMed records.

For more information, please see:

PubMed Commons Homepage

NCBI Insights Blog Posts:

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New human genome assembly (GRCh38) released!

On December 24th, the Genome Reference Consortium (GRC) submitted a new assembly for the human genome (GRCh38) to GenBank.  These data are now available in the Assembly database with accession GCA_000001405.15and are also available on the FTP site.  Please note the GRC provides these assemblies as unannotated sequences.

Now that the GRC sequences are available in GenBank, our Reference Sequence (RefSeq) Genome Annotation Group has downloaded these sequences and has begun processing them using our eukaryotic annotation pipeline. These resulting human chromosome sequences will continue to have the RefSeq accessions NC_000001-NC_000024, but their versions will increment as the update to the GRCh38 assembly includes a sequence change for all chromosomes. The process of annotating the human genome generally takes about 2 weeks.  When this is complete, we will incorporate these sequences into various analysis and display tools, such as human genome BLAST, NCBI Remapping Service, and various genome viewers.  Thus, at the end of this process each chromosome will be represented by both an unannotated sequence in GenBank (the original GRC data) and an annotated sequence in the RefSeq collection.

Please check back frequently for updates on the NCBI News and our social media sites (NCBI Twitter Channel, NCBI Facebook Page, NCBI Announce RSS Feed, NCBI Announce Email ListServ) as this process unfolds.

In addition, we have a series of posts on the NCBI Insights Blog site on topics such as how NCBI processes genome annotations, a tip to remap annotations from older assemblies to GRCh38, and highlighting some loci that have changed significantly in the new assembly.

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NCBI Insights blog post: Saved Searches and E-mail Alerts

As part of the My NCBI service, PubMed and other Entrez databases allow users to save searches and then receive regular e-mail alerts about new records retrieved by that search. Please see the new NCBI Insights blog post for details about setting up these searches and alerts.

For more information, see the following:

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NCBI Video: Submitting manuscripts on NIHMS

NCBI’s latest YouTube video takes you through the manuscript submission process on the NIH Manuscript Submission System (NIHMS), step-by-step. NIHMS enables publishers, authors, and principal investigators to submit manuscripts for processing and archiving in PubMed Central.

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New NCBI Handbook chapters: Eukaryotic and prokaryotic genome annotation pipelines

In order to increase the utility of genomic information, we provide gene annotation and other features on Reference Sequence (RefSeq) genome records. Genome annotation is a multi-step process that includes prediction of protein-coding genes, as well as other functional genome units such as structural RNAs, tRNAs, small RNAs, pseudogenes, control regions, direct and inverted repeats, insertion sequences, transposons, and other mobile elements.

Depending upon the genome, the identification of key genomic features and their locations on RefSeq genome records are provided by outside sources (the submitter’s annotation copied from the GenBank genomic sequence records or curated annotation provided by a model organism database, like FlyBase or WormBase), or are generated by annotation pipelines developed at NCBI specifically for eukaryotic or for prokaryotic genomes.

An overview of each pipeline is available in our web documentation In addition to web documentation of our eukaryotic genome annotation pipeline and prokaryotic genome annotation process.

Our newest NCBI Handbook Chapters on the eukaryotic and prokaryotic annotation pipelines describe the processes in greater detail, including information on algorithms, history, annotation standards and special considerations like multiple annotation assemblies:

We also provide eukaryotic genome annotation policies and the status of genomes in the current pipeline, as well as information about prokaryotic genome annotation standards.

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New NCBI Insights Blog Post: Joining PubMed Commons - A step-by-step guide

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PubMed Commons is a new system that enables researchers to share their opinions about scientific publications indexed in the PubMed database. Participation in PubMed Commons requires users with My NCBI accounts to join before they can view or add comments. A new NCBI Insights Blog post describes how to join PubMed Commons.

For more information, please see:

PubMed Commons Homepage

"Joining PubMed Commons: A Step-by-step Guide"

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Brigham and Women's Physician Resource Center: Mesothelioma: Extrapleural Pneumonectomy

Please click the link below to watch the video on Mesothelioma Extrapleural Pneumonectomy.
Brigham and Women's Physician Resource Center: Mesothelioma: Extrapleural Pneumonectomy

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