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1.  Bending the Cost Curve in Cancer Care 
The New England journal of medicine  2011;364(21):2060-2065.
doi:10.1056/NEJMsb1013826
PMCID: PMC4042405  PMID: 21612477
2.  Association between Body-Mass Index and Risk of Death in More Than 1 Million Asians 
The New England journal of medicine  2011;364(8):719-729.
Background
Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin.
Methods
We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors.
Results
In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range — by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI.
Conclusions
Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis.
doi:10.1056/NEJMoa1010679
PMCID: PMC4008249  PMID: 21345101
3.  ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's Lymphoma 
The New England journal of medicine  2011;366(5):399-408.
BACKGROUND
Chemotherapy plus radiation treatment is effective in controlling stage IA or IIA nonbulky Hodgkin’s lymphoma in 90% of patients but is associated with late treatment-related deaths. Chemotherapy alone may improve survival because it is associated with fewer late deaths.
METHODS
We randomly assigned 405 patients with previously untreated stage IA or IIA non-bulky Hodgkin’s lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy. Patients in the ABVD-only group, both those with a favorable risk profile and those with an unfavorable risk profile, received four to six cycles of ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. The primary end point was 12-year overall survival.
RESULTS
The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P = 0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P = 0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P = 0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkin’s lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkin’s lymphoma or early toxic effects from the treatment and 20 were related to another cause.
CONCLUSIONS
Among patients with Hodgkin’s lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes. (Funded by the Canadian Cancer Society and the National Cancer Institute; HD.6 ClinicalTrials.gov number, NCT00002561.)
doi:10.1056/NEJMoa1111961
PMCID: PMC3932020  PMID: 22149921
4.  Hypoxia and Inflammation 
The New England journal of medicine  2011;364(7):656-665.
doi:10.1056/NEJMra0910283
PMCID: PMC3930928  PMID: 21323543
5.  Outcomes of Hepatitis C Treatment by Primary Care Providers 
The New England journal of medicine  2011;364(23):10.1056/NEJMoa1009370.
Background
The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for complex health problems such as hepatitis C virus (HCV) infection for underserved populations. Using videoconferencing technology, ECHO trains primary care providers to treat complex diseases.
Methods
A prospective cohort study compared treatment of HCV at the University of New Mexico (UNM) HCV clinic to treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 treatment naive patients with chronic HCV were enrolled. The primary end point was a sustained viral response (SVR).
Results
The rate of SVR was 57.5% (84/146) for patients treated at UNM and 58.2% (152 /261) at ECHO sites (P=0.89); difference between SVR rates 0.7% (95% CI -9.2%, 10.7%). In genotype 1 infection the SVR rate was 45.8% (38 /83) at UNM and 49.7% (73 /147) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the UNM HCV clinic cohort and 6.9% of the ECHO cohort.
Conclusions
This study demonstrates that the ECHO model is an effective way to treat HCV in underserved communities. Implementation of this model would allow other states and nations to treat more patients with HCV.
doi:10.1056/NEJMoa1009370
PMCID: PMC3820419  PMID: 21631316
6.  Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection 
The New England journal of medicine  2011;365(11):10.1056/NEJMoa1014463.
BACKGROUND
Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon–ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, −10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations.
METHODS
We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon–ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48.
RESULTS
Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, −2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001).
CONCLUSIONS
In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon–ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.)
doi:10.1056/NEJMoa1014463
PMCID: PMC3809077  PMID: 21916639
7.  Stem Cells and Eye Development 
The New England journal of medicine  2011;365(4):370-372.
doi:10.1056/NEJMcibr1105280
PMCID: PMC3805038  PMID: 21793749
8.  IMAGES IN CLINICAL MEDICINE 
doi:10.1056/NEJMicm1006035
PMCID: PMC3805040  PMID: 21345097
9.  Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk 
The New England journal of medicine  2011;364(6):524-534.
Background
The use of direct-to-consumer genomewide profiling to assess disease risk is controversial, and little is known about the effect of this technology on consumers. We examined the psychological, behavioral, and clinical effects of risk scanning with the Navigenics Health Compass, a commercially available test of uncertain clinical validity and utility.
Methods
We recruited subjects from health and technology companies who elected to purchase the Health Compass at a discounted rate. Subjects reported any changes in symptoms of anxiety, intake of dietary fat, and exercise behavior at a mean (±SD) of 5.6±2.4 months after testing, as compared with baseline, along with any test-related distress and the use of health-screening tests.
Results
From a cohort of 3639 enrolled subjects, 2037 completed follow-up. Primary analyses showed no significant differences between baseline and follow-up in anxiety symptoms (P = 0.80), dietary fat intake (P = 0.89), or exercise behavior (P = 0.61). Secondary analyses revealed that test-related distress was positively correlated with the average estimated lifetime risk among all the assessed conditions (β = 0.117, P<0.001). However, 90.3% of subjects who completed follow-up had scores indicating no test-related distress. There was no significant increase in the rate of use of screening tests associated with genomewide profiling, most of which are not considered appropriate for screening asymptomatic persons in any case.
Conclusions
In a selected sample of subjects who completed follow-up after undergoing consumer genomewide testing, such testing did not result in any measurable short-term changes in psychological health, diet or exercise behavior, or use of screening tests. Potential effects of this type of genetic testing on the population at large are not known. (Funded by the National Institutes of Health and Scripps Health.)
doi:10.1056/NEJMoa1011893
PMCID: PMC3786730  PMID: 21226570
10.  Microtubules, Axonal Transport, and Neuropathy 
The New England journal of medicine  2011;365(24):2330-2332.
doi:10.1056/NEJMcibr1112481
PMCID: PMC3776444  PMID: 22168648
11.  Perilipin Deficiency and Autosomal Dominant Partial Lipodystrophy 
The New England journal of medicine  2011;364(8):740-748.
Summary
Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.
doi:10.1056/NEJMoa1007487
PMCID: PMC3773916  PMID: 21345103
12.  Diagnosis of Smoldering Multiple Myeloma 
The New England journal of medicine  2011;365(5):474-475.
doi:10.1056/NEJMc1106428
PMCID: PMC3773467  PMID: 21812699
13.  Acute HIV-1 Infection 
The New England journal of medicine  2011;364(20):1943-1954.
In 2009, the United Nations Estimated that 33.2 Million People worldwide were living with human immunodeficiency virus type 1 (HIV-1) infection and that 2.6 million people had been newly infected.1 The need for effective HIV-1 prevention has never been greater. In this review, we address recent critical advances in our understanding of HIV-1 transmission and acute HIV-1 infection. Fourth-generation HIV-1 testing, now available worldwide,2,3 will allow the diagnosis of infection in many patients and may lead to new treatments and opportunities for prevention.
doi:10.1056/NEJMra1011874
PMCID: PMC3771113  PMID: 21591946
14.  A Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele 
The New England journal of medicine  2011;364(11):993-1004.
Background
Prenatal repair of myelomeningocele, the most common form of spina bifida, may result in better neurologic function than repair deferred until after delivery. We compared outcomes of in utero repair with standard postnatal repair.
Methods
We randomly assigned eligible women to undergo either prenatal surgery before 26 weeks of gestation or standard postnatal repair. One primary outcome was a composite of fetal or neonatal death or the need for placement of a cerebrospinal fluid shunt by the age of 12 months. Another primary outcome at 30 months was a composite of mental development and motor function.
Results
The trial was stopped for efficacy of prenatal surgery after the recruitment of 183 of a planned 200 patients. This report is based on results in 158 patients whose children were evaluated at 12 months. The first primary outcome occurred in 68% of the infants in the prenatal-surgery group and in 98% of those in the postnatal-surgery group (relative risk, 0.70; 97.7% confidence interval [CI], 0.58 to 0.84; P<0.001). Actual rates of shunt placement were 40% in the prenatal-surgery group and 82% in the postnatal-surgery group (relative risk, 0.48; 97.7% CI, 0.36 to 0.64; P<0.001). Prenatal surgery also resulted in improvement in the composite score for mental development and motor function at 30 months (P = 0.007) and in improvement in several secondary outcomes, including hindbrain herniation by 12 months and ambulation by 30 months. However, prenatal surgery was associated with an increased risk of preterm delivery and uterine dehiscence at delivery.
Conclusions
Prenatal surgery for myelomeningocele reduced the need for shunting and improved motor outcomes at 30 months but was associated with maternal and fetal risks. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00060606.)
doi:10.1056/NEJMoa1014379
PMCID: PMC3770179  PMID: 21306277
15.  Boceprevir for Untreated Chronic HCV Genotype 1 Infection 
The New England journal of medicine  2011;364(13):1195-1206.
BACKGROUND
Peginterferon–ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.
METHODS
We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the leadin period). Subsequently, group 1 (the control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon–ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.
RESULTS
A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P = 0.04), and in 29 of the 55 patients (53%) in group 3 (P = 0.004). In group 2, a total of 44% of patients received peginterferon–ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.
CONCLUSIONS
The addition of boceprevir to standard therapy with peginterferon–ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.)
doi:10.1056/NEJMoa1010494
PMCID: PMC3766849  PMID: 21449783
16.  Norovirus Vaccine against Experimental Human Norwalk Virus Illness 
The New England journal of medicine  2011;365(23):2178-2187.
Background
Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection.
Methods
We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms.
Results
Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Nor-walk virus–specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P = 0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P = 0.05).
Conclusions
This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.)
doi:10.1056/NEJMoa1101245
PMCID: PMC3761795  PMID: 22150036
17.  Discussing Overall Prognosis with the Very Elderly 
The New England journal of medicine  2011;365(23):2149-2151.
doi:10.1056/NEJMp1109990
PMCID: PMC3760676  PMID: 22150033
18.  The Tumor Lysis Syndrome 
The New England journal of medicine  2011;365(6):571-574.
doi:10.1056/NEJMc1106641#SA1
PMCID: PMC3740722  PMID: 21830982
20.  Interleukin-2 and Regulatory T Cells in Graft-versus-Host Disease 
The New England journal of medicine  2011;365(22):2055-2066.
Background
Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD.
Methods
In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×106, 1×106, or 3×106 IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period.
Results
A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×106 IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100).
Conclusions
Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana–Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.)
doi:10.1056/NEJMoa1108188
PMCID: PMC3727432  PMID: 22129252
21.  A RANDOMIZED TRIAL OF HORSE VERSUS RABBIT ANTITHYMOCYTE GLOBULIN IN SEVERE ACQUIRED APLASTIC ANEMIA 
The New England journal of medicine  2011;365(5):430-438.
Background
In severe acquired aplastic anemia, hematopoietic failure is the result of immune mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem cell transplantation and improves blood counts and survival. While horse ATG is standard, rabbit ATG is more potent at depleting peripheral blood lymphocytes and is preferred in other clinical circumstances.
Methods
From December 2005 to July 2010, we performed a randomized trial comparing these two different ATG formulations at conventional regimens. Patients were treated at a single government facility. Primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to accrue 60 patients per arm and powered to detect a 25% difference in response rate.
Results
There was a large, unexpected difference in hematologic responses at 6 months in favor of horse ATG (68%; 95% confidence interval (CI), 56%–80%) compared to rabbit ATG (37%; 95% CI, 24%–49%; p<0.001). Overall survival at 3 years also differed, with 96% (95% CI, 90%–100%) surviving in the horse ATG group compared to 76% (95% CI, 61%–95%; p=0.04) in the rabbit ATG group when stem cell transplantation was censored, and 94% (95% CI, 88%–100%) for horse ATG and 70% (95% CI, 56%–86%; p=0.008) for rabbit ATG when stem cell transplantation events were not censored.
Conclusions
In a randomized study, rabbit ATG was markedly inferior to horse ATG as first treatment in severe aplastic anemia as measured by hematologic response and survival.
doi:10.1056/NEJMoa1103975
PMCID: PMC3721503  PMID: 21812672
22.  PARP and Cancer — If It's Broke, Don't Fix It 
The New England journal of medicine  2011;364(3):277-279.
doi:10.1056/NEJMe1012546
PMCID: PMC3712751  PMID: 21208102
23.  MYO1E MUTATIONS AND CHILDHOOD FAMILIAL FOCAL SEGMENTAL GLOMERULOSCLEROSIS 
The New England journal of medicine  2011;365(4):295-306.
Background
Focal segmental glomerulosclerosis (FSGS) is a kidney disease that presents with nephrotic syndrome and is often resistant to glucocorticosteroids and progresses to end-stage kidney disease in 50–70% of patients. Genetic studies in familial FSGS indicate that it is a disease of the podocytes, major components of the glomerular filtration barrier. However the molecular cause of over half of primary FSGS is unknown, and effective treatments have been elusive.
Methods
We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive linkage area in a family with autosomal recessive FSGS and sequenced a newly discovered gene in 52 unrelated FSGS patients. Immunohistochemistry was performed in human kidney biopsies and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified.
Results
Two mutations (A159P and Y695X) in MYO1E, encoding the non-muscle class I myosin, myosin 1E (Myo1E), which segregated with FSGS in two independent pedigrees were identified. Patients were homozygous for the mutations and were resistant to glucocorticosteroids. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney biopsies in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and the tail domains of Myo1E.
Conclusions
MYO1E mutations lead to childhood onset steroid-resistant FSGS. These data support a role of Myo1E in podocyte function and the consequent integrity of the glomerular permselectivity barrier.
doi:10.1056/NEJMoa1101273
PMCID: PMC3701523  PMID: 21756023
25.  BRAF MUTATIONS IN HAIRY CELL LEUKEMIA 
The New England journal of medicine  2011;364(24):2305-2315.
Background
Hairy cell leukemia (HCL) is a well defined clinico-pathological entity whose underlying genetic lesion is still obscure.
Methods
We searched for HCL-associated mutations by massively parallel sequencing of the whole exome of leukemic and matched normal mononuclear cells purified from the peripheral blood of one patient with HCL.
Results
Whole exome sequencing identified 5 missense somatic clonal mutations that were confirmed at Sanger sequencing, including a heterozygous V600E mutation involving the BRAF gene. Since the BRAF V600E mutation is oncogenic in other tumors, further analyses were focused on this genetic lesion. Sanger sequencing detected mutated BRAF in 46/46 additional HCL patients (47/47 including the index case; 100%). None of the 193 peripheral B-cell lymphomas/leukemias other than HCL that were investigated carried the BRAF V600E mutation, including 36 cases of splenic marginal zone lymphomas and unclassifiable splenic lymphomas/leukemias. Immunohistological and Western blot studies showed that HCL cells express phospho-MEK and phospho-ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic cells from 5 HCL patients with PLX-4720, a specific inhibitor of active BRAF, led to marked decrease of phosphorylated ERK and MEK.
Conclusions
The BRAF V600E mutation was present in all HCL patients investigated. This finding may have relevant implications for the pathogenesis, diagnosis and targeted therapy of HCL (Funded by the Associazione Italiana Ricerca Cancro and others).
doi:10.1056/NEJMoa1014209
PMCID: PMC3689585  PMID: 21663470

Results 1-25 (90)