Genetic continuity and change among the Indigenous peoples of California.

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2-4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.

FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation.

On August 17, 2011, the U.S. Food and Drug Administration (FDA) approved vemurafenib tablets (Zelboraf, Hoffmann-LaRoche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAF(V600E) mutation as detected by an FDA-approved test. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Inc.) was approved concurrently. An international, multicenter, randomized, open-label trial in 675 previously untreated patients with BRAF(V600E) mutation-positive unresectable or metastatic melanoma allocated 337 patients to receive vemurafenib, 960 mg orally twice daily, and 338 patients to receive dacarbazine, 1,000 mg/m(2) intravenously every 3 weeks. Overall survival was significantly improved in patients receiving vemurafenib [HR, 0.44; 95% confidence interval (CI), 0.33-0.59; P < 0.0001]. Progression-free survival was also significantly improved in patients receiving vemurafenib (HR, 0.26; 95% CI, 0.20-0.33; P < 0.0001). Overall response rates were 48.4% and 5.5% in the vemurafenib and dacarbazine arms, respectively. The most common adverse reactions (≥30%) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea. Cutaneous squamous cell carcinomas or keratoacanthomas were detected in approximately 24% of patients treated with vemurafenib. Other adverse reactions included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities.

Sociopolitical effects of bow and arrow technology in prehistoric coastal California.

Bow and arrow technology spread across California between ∼AD 250 and 1200, first appearing in the intermountain deserts of the Great Basin and later spreading to the coast. We critically evaluate the available data for the initial spread in bow and arrow technology and examine its societal effects on the well-studied Northern Channel Islands off the coast of Southern California. The introduction of this technology to these islands between AD 650 and 900 appears to predate the appearance of hereditary inequality between AD 900 and 1300. We conclude, based on the available data, that this technology did not immediately trigger intergroup warfare. We argue that the introduction of the bow and arrow contributed to sociopolitical instabilities that were on the rise within the context of increasing population levels and unstable climatic conditions, which stimulated intergroup conflict and favored the development of hereditary inequality. Population aggregation and economic intensification did occur with the introduction of the bow and arrow. This observation is consistent with the hypothesis that social coercion via intra-group "law enforcement" contributed to changes in societal scale that ultimately resulted in larger groups that were favored in inter-group conflict. We argue that the interplay between intra-group "law enforcement" and inter-group warfare were both essential for the ultimate emergence of social inequality between AD 900 and 1300.

Genetic analysis of early holocene skeletal remains from Alaska and its implications for the settlement of the Americas.

Mitochondrial and Y-chromosome DNA were analyzed from 10,300-year-old human remains excavated from On Your Knees Cave on Prince of Wales Island, Alaska (Site 49-PET-408). This individual's mitochondrial DNA (mtDNA) represents the founder haplotype of an additional subhaplogroup of haplogroup D that was brought to the Americas, demonstrating that widely held assumptions about the genetic composition of the earliest Americans are incorrect. The amount of diversity that has accumulated in the subhaplogroup over the past 10,300 years suggests that previous calibrations of the mtDNA clock may have underestimated the rate of molecular evolution. If substantiated, the dates of events based on these previous estimates are too old, which may explain the discordance between inferences based on genetic and archaeological evidence regarding the timing of the settlement of the Americas. In addition, this individual's Y-chromosome belongs to haplogroup Q-M3*, placing a minimum date of 10,300 years ago for the emergence of this haplogroup.

Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma.

PURPOSE: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. EXPERIMENTAL DESIGN: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). RESULTS: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. CONCLUSIONS: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).

Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen.

PURPOSE: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. EXPERIMENTAL DESIGN: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. RESULTS: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. CONCLUSIONS: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.

Native American mtDNA prehistory in the American Southwest.

This study examines the mtDNA diversity of the proposed descendants of the multiethnic Hohokam and Anasazi cultural traditions, as well as Uto-Aztecan and Southern-Athapaskan groups, to investigate hypothesized migrations associated with the Southwest region. The mtDNA haplogroups of 117 Native Americans from southwestern North America were determined. The hypervariable segment I (HVSI) portion of the control region of 53 of these individuals was sequenced, and the within-haplogroup diversity of 18 Native American populations from North, Central, and South America was analyzed. Within North America, populations in the West contain higher amounts of diversity than in other regions, probably due to a population expansion and high levels of gene flow among subpopulations in this region throughout prehistory. The distribution of haplogroups in the Southwest is structured more by archaeological tradition than by language. Yumans and Pimans exhibit substantially greater genetic diversity than the Jemez and Zuni, probably due to admixture and genetic isolation, respectively. We find no evidence of a movement of mtDNA lineages northward into the Southwest from Central Mexico, which, in combination with evidence from nuclear markers, suggests that the spread of Uto-Aztecan was facilitated by predominantly male migration. Southern Athapaskans probably experienced a bottleneck followed by extensive admixture during the migration to their current homeland in the Southwest.