Human genome project: Best is yet to come

Former US president Bill Clinton called it the “most important, most wondrous map ever produced by humankind”. To then UK prime minister Tony Blair, it was a “breakthrough that takes humankind across a frontier and into a new era”. His science minister David Sainsbury said: “We now have the possibility of achieving all we ever hoped for from medicine.” When Nature published a 62-page article on 15 February 2001 titled ‘Initial sequencing and analysis of the human genome’ it is not difficult to see why the world got excited. Perhaps, even, a little overexcited. One of our editors, Henry Gee, penned a newspaper piece at the time that promised, by 2099, “genomics will allow us to alter entire organisms out of all recognition, to suit our needs and tastes … [and] will allow us to fashion the human form into any conceivable shape. We will have extra limbs, if we want them — maybe even wings to fly.”

As Eric Lander, director of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, and the first author on that 2001 paper, writes on page 187 of this issue: “The human genome has had a certain tendency to incite passion and excess.” A decade on, Lander notes, the pattern continues, with “a front-page news story on the tenth anniversary of the announcement that chided genome scientists for not yet having cured most diseases”. The 2001 sequence was always a milestone on the journey to better medical care, rather than a destination. The ten-year anniversary of the publication in Nature and Science of sequences prepared respectively by the international Human Genome Project and Celera Genomics, now of Alameda, California, provides another — as well as an opportunity to reflect on progress.

Some things have undoubtedly changed. Nature‘s Editorial page in the 15 February 2001 issue examined not the scientific and medical promise of the genome sequence, but the challenge of public access to information gathered by the commercial genomics sector. Acrimony over the differing public and private approaches has since faded; concerns over access to genomic data now centre on privacy issues.

Has medical progress been slower than was expected at the time? In an article on page 204, Eric Green and Mark Guyer of the US National Human Genome Research Institute in Bethesda, Maryland, offer an “updated vision” of the prospects for genomic medicine. “Significant change rarely comes quickly,” they write. “Although genomics has already begun to improve diagnostics and treatments in a few circumstances, profound improvements in the effectiveness of healthcare cannot realistically be expected for many years.” Research is not enough, they say, and new policies and practices as part of an expanded global effort are needed too.

The sequencing of the human genome was in many ways a triumph for technology as much as it was for science. That technology has continued to develop over the past decade, which Elaine Mardis of the Genome Center at Washington University in St Louis describes in an article starting on page 198 as a “remarkable sequencing technology explosion”.

Massively parallel sequencing technology allows questions to be asked and answered with “unprecedented speed and resolution”, she says. “The continuing upward trajectory of sequencing technology development is enabling clinical applications that are aimed at improving medical diagnosis and treatment.” A useful example is the development of genome-wide association studies to probe the underlying genetic landscape of some common diseases.

More than a decade ago, Michael Dexter, then head of the UK Wellcome Trust, which took part in the Human Genome Project, branded the genome sequence as the outstanding achievement of human history, eclipsing the significance both of the Moon landings and of the invention of the wheel. It is too early for that history to be written. For the genome sequence to be a true success, we must yet ensure that greater achievements are built on it.

source: nature

The hippocampus in major depression

Major depressive disorder (MDD) has until recently been conceptualized as an episodic disorder associated with ‘chemical imbalances’ but no permanent brain changes. Evidence has emerged in the past decade that MDD is associated with small hippocampal volumes. This paper reviews the clinical and biological correlates of small hippocampal volumes based on literature searches of PubMed and EMBASE and discusses the ways in which these data force a re-conceptualization of MDD. Preclinical data describe the molecular and cellular effects of chronic stress and antidepressant treatment on the hippocampus, providing plausible mechanisms through which MDD might be associated with small hippocampal volumes. Small hippocampal volumes are associated with poor clinical outcome and may be a mechanism through which MDD appears to be a risk factor for Alzheimer’s disease. The pathways through which stress may be linked to MDD, the emergence of chronicity or treatment resistance in MDD and the association between MDD and memory problems may be at least partially understood by dissecting the association with depression and changes in the hippocampus. MDD must be re-conceived as a complex illness, associated with persistent morphological brain changes that are detectable before illness onset and which may be modified by clinical and treatment variables.

source: nature psyciatry

Phosphoprotein pathway profiling of ovarian carcinoma for the identification of potential new targets for therapy

Advances in predicting responses to therapies in ovarian cancer have not matched progress seen in other solid-organ tumours: ovarian cancer remains a poor-prognosis disease. There has been a paradigm shift in molecular therapeutics away from targeting individual molecules to whole biological pathways. The aim of this study was to quantitatively measure the activation state of druggable oncogenic pathways by generating a phosphoprotein profile in cancer tissues, in order to establish associations with clinicopathological parameters and to identify treatment groups for targeted therapy. In total we analysed the expression of ten phosphoproteins within eight signalling pathways (PI3K, MAPK, β-catenin, STAT, NFκB, ER, cell cycle and DNA damage response), proliferation (phospho-histone H3 and Ki67) and apoptosis (activated caspase 3), in two independent cohorts of ovarian cancers using quantitative immunofluorescence image analysis. Data were analysed by unsupervised and K-means clustering to determine new biologically relevant groups. Expression of markers of the five main pathways deregulated by mutation or copy number changes was different between histological subtypes. Four main clusters with distinct phosphoprotein profiles were identified, which were significantly associated with survival in univariate analysis, and which had distinct patterns of pathway expression reproducible between clinical cohorts. These pathway profiles suggest novel therapeutic regimens for the treatment of ovarian cancer, such as MAPK-inhibition in serous or clear cell carcinomas, or combined inhibition of STAT, NFκB and WNT signalling.

source: science direct

Three-Dimensional High-Frequency Backscatter and Envelope Quantification of Cancerous Human Lymph Nodes

Quantitative imaging methods using high-frequency ultrasound (HFU) offer a means of characterizing biological tissue at the microscopic level. Previously, high-frequency, 3-D quantitative ultrasound (QUS) methods were developed to characterize 46 freshly-dissected lymph nodes of colorectal-cancer patients. 3-D ultrasound radiofrequency data were acquired using a 25.6-MHz center-frequency transducer and each node was inked before tissue fixation to recover orientation after sectioning for 3-D histological evaluation. Backscattered echo signals were processed using 3-D cylindrical regions-of-interest (ROIs) to yield four QUS estimates associated with tissue microstructure (i.e., effective scatterer size, acoustic concentration, intercept and slope). These QUS estimates, obtained by parameterizing the backscatter spectrum, showed great potential for cancer detection. In the present study, these QUS methods were applied to 112 lymph nodes from 77 colorectal and gastric cancer patients. Novel QUS methods parameterizing the envelope statistics of the ROIs using Nakagami and homodyned-K distributions were also developed; they yielded four additional QUS estimates. The ability of these eight QUS estimates to classify lymph nodes and detect cancer was evaluated using receiver operating characteristics (ROC) curves. An area under the ROC curve of 0.996 with specificity and sensitivity of 95% were obtained by combining effective scatterer size and one envelope parameter based on the homodyned-K distribution. Therefore, these advanced 3-D QUS methods potentially can be valuable for detecting small metastatic foci in dissected lymph nodes.

source: science direct

A Patch for Agitation in Smoking Schizophrenia Patients

Adding nicotine patches to usual treatment reduces agitation in newly admitted patients with schizophrenia who smoke.

Many patients with schizophrenia smoke cigarettes, but many treatment facilities now ban smoking. Schizophrenia patients who smoke face this additional stressor when admitted to smoke-free hospitals. This double-blind, randomized, controlled trial of nicotine replacement therapy involved 40 adult smokers with schizophrenia and at least some agitation who were admitted to a smoke-free psychiatric emergency unit.

The patients received nicotine (21 mg) or placebo patches plus their ongoing antipsychotic medications or newly administered oral or intramuscular olanzapine (5 or 10 mg) or intramuscular haloperidol (5 mg). Compared with placebo, nicotine was associated with 33% less agitation at 4 hours and 23% less agitation at 24 hours. The intervention showed a dose–response curve inversely related to the degree of nicotine dependence. The difference in agitation between nicotine replacement and placebo was stronger in patients with who smoked less than in those who smoked more.

Comment: Patients who smoked more might have had a smaller response to the nicotine patch because the 21-mg dose was insufficient; higher doses might be more effective for them. Future research may yield a more sophisticated understanding of such dose–response relationships and may explore potential drug–drug interactions between nicotine and various antipsychotics. The authors conjecture that nicotine might reduce aggression even in nonsmoking patients, but this hypothesis has yet to be clinically tested.

Joel Yager, MD

Published in Journal Watch Psychiatry February 18, 2011

Tenofovir for HIV and Hepatitis B Virus Coinfection

Long-term use of tenofovir as part of antiretroviral therapy was safe and effective in reducing HBV DNA levels.

Tenofovir is an effective first-line agent for patients with hepatitis B virus (HBV) infection (JW Gastroenterol Jan 23 2009). The drug also seems to be effective for patients who are coinfected with HBV and HIV, although follow-up evaluations have been limited.

In this multicenter, prospective, cohort study, Dutch researchers followed 102 HBV/HIV patients (mean age, 42; 90% men) for a median of 55 months (interquartile range, 42–64 months). At baseline, all patients had received tenofovir as part of antiretroviral therapy for ≥6 months, 80% had detectable HBV DNA (mean level, 7 log10 IU/mL), 66% were positive for hepatitis B e antigen (HBeAg), 49% were treated previously with lamivudine, and 32% had evidence of lamivudine resistance. During the study period, patients received tenofovir plus concomitant lamivudine or emtricitabine. The primary endpoint was virologic response, defined as HBV DNA level <20 IU/mL. Renal toxicity was monitored with serum creatinine levels.

Among HBeAg-positive patients, 92% had virologic response after 5 years of treatment (response was similar in patients with or without lamivudine resistance), 46% achieved loss of HBeAg, and 12% achieved loss of hepatitis B surface antigen (HBsAg). Among HBeAg-negative patients, 100% achieved virologic response after 4 years, and 13% achieved loss of HBsAg. Only one patient developed resistance, and three patients discontinued tenofovir because of increased serum creatinine levels.

Comment: This long-term study of tenofovir in HBV/HIV coinfected patients demonstrates excellent safety and efficacy similar to findings in HBV monoinfected patients. These results were the same for patients with or without baseline lamivudine resistance. This study validates the practice of using tenofovir as the foundation of antiretroviral therapy in HBV/HIV coinfected patients.

Atif Zaman, MD, MPH

Published in Journal Watch Gastroenterology February 18, 2011

Severe H1N1 Influenza Infection: Hold the Corticosteroids!

An observational European study shows that corticosteroids increased risk for pneumonia and conferred no mortality benefit in patients with severe H1N1 infection.

Use of corticosteroids to mitigate the cytokine storm that might contribute to poor outcomes in otherwise healthy people with pandemic H1N1 influenza infection is controversial, even in those with acute respiratory distress syndrome (ARDS). In a prospective observational study, investigators evaluated the effect of corticosteroids on outcomes in 220 intensive care unit (ICU) patients who were enrolled in the European Society of Intensive Care Medicine H1N1 registry from June 2009 through February 2010. H1N1 influenza A infection was confirmed in 194 patients, probable in 2, and suspected in 24. All patients received antivirals, and 78% were mechanically ventilated.

The 126 patients (57%) who received corticosteroids on ICU admission (dosages equivalent to >24 mg/day of methylprednisone or >30 mg/day of prednisone), compared to patients who did not, were significantly older, more likely to have comorbid pulmonary conditions, and more likely to be chronic corticosteroid users. Although patients who received corticosteroids on ICU admission were significantly more likely to contract hospital-acquired pneumonia (26% vs. 14%; odds ratio, 2.2) and to die in the ICU (46% vs. 18%; OR, 3.8), the association with mortality was no longer present after adjustment for severity of disease and other confounding variables (age, asthma, chronic obstructive pulmonary disease, chronic corticosteroid use). Results were similar when the analysis was limited to the 74% of patients with ARDS.

Comment: This study is limited by its observational nature, variable dosing of oseltamivir, and that patients who received “rescue” corticosteroids after ICU admission were not considered part of the corticosteroid group. For now, corticosteroids do not seem helpful — and might be harmful — in patients with H1N1 influenza.

Kristi L. Koenig, MD, FACEP

Published in Journal Watch Emergency Medicine February 18, 2011

A new light-emitting material, changes structure to glow

Researchers have developed the first organic compounds, capable of emitting pretty colors such as blue, yellow-green and orange – and all the material has to do is change its structure.

Normally, organic light emitting diodes (OLEDs) are made with precious metals. Even some sensors can contain metals such as iridium. But the new material can be made without metal, and could potentially cut the cost of producing the material for consumer products.

Just mix carbon, oxygen, chlorine and bromine together, expose the material to ultraviolet light… to make this new light-emitting material.

Normally, the ability to emit light has been limited to non-organic compounds and the materials with the rare metals.

But researchers at the University of Michigan figured out how to make organic compounds emit light too. The compounds were made with aromatic carbonyls. Its molecules are packed close together and it’s this tight structure that gives the material its impressive range of color.

Jinsang Kim, a Michigan researcher, said in a statement:

Purely organic materials haven’t been able to generate meaningful phosphorescence emissions. We believe this is the first example of an organic that can compete with an organometallic in terms of brightness and color tuning capability.

Soon, the OLEDs in your gadget could be made a little greener… with a little less metal. If commercialized and put into cell phone and camera screens, it would bring down the cost.

It’s cheaper simply because the organic material wouldn’t need any metal to glow. The researchers think the material could potentially shake up the LED and solid-state lighting industry. But it’s too soon to tell now. Either way, it’s an impressive discovery and worth keeping an eye on. The study was published in Nature Chemistry.

phosphorussource: smartplanet