Mitochondrial DNA diversity in the Khattak and Kheshgi of the Peshawar Valley, Pakistan.

The strategic location of Pakistan and its presence at the crossroads of Asia has resulted in it playing a central role in both prehistoric and historic human migratory events, thereby linking and facilitating contacts between the inhabitants of the Middle East, Central Asia, China and South Asia. Despite the importance of this region and its inhabitants for our understanding of modern human origins and population dispersals, the nature of mitochondrial DNA (mtDNA) variation among members of the myriad populations of this area has largely been unexplored. Here, we report mtDNA control region sequences in 58 individuals from the Khattak and the Kheshgi, two major Pakhtun tribes residing within the Peshawar Valley of northwestern Pakistan. The results reveal that these ethnic groups are genetically heterogeneous, having 55.7% West Eurasian, 33.9% South Asian and 10.2% East Asian haplogroups. The genetic diversity observed for the Kheshgi was somewhat higher than that of the Khattak. A multidimensional scaling plot based on haplogroup frequencies for the Khattak, Kheshgi and neighboring populations indicates that the Khattak have close affinities with Baluch, Uzbek and Kazak populations but are only distantly related to the Kheshgi and other Pakistani populations. By contrast, the Kheshgi cluster closely with other Pakhtun or Pathan populations of Pakistan, suggesting a possible common maternal gene pool shared amongst them. These mtDNA data allow us to begin reconstructing the origins of the Khattak and Kheshgi and describe their complex interactions with populations from the surrounding regions.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial.

BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

High Y-chromosomal Differentiation Among Ethnic Groups of Dir and Swat Districts, Pakistan.

The ethnic groups that inhabit the mountainous Dir and Swat districts of northern Pakistan are marked by high levels of cultural and phenotypic diversity. To obtain knowledge of the extent of genetic diversity in this region, we investigated Y-chromosomal diversity in five population samples representing the three main ethnic groups residing within these districts, including Gujars, Pashtuns and Kohistanis. A total of 27 Y-chromosomal short tandem repeats (Y-STRs) and 331 Y-chromosomal single nucleotide polymorphisms (Y-SNPs) were investigated. In the Y-STRs, we observed very high and significant levels of genetic differentiation in nine of the 10 pairwise between-group comparisons (RST 0.179-0.746), and the differences were mirrored in the Y-SNP haplogroup frequency distribution. No genetic differences were found between the two Pashtun subethnic groups Tarklanis and Yusafzais (RST = 0.000). Utmankhels, also considered Pashtuns culturally, were not closely related to any of the other population samples (RST 0.451-0.746). Thus, our findings provide examples of both associations and dissociations between cultural and genetic legacies. When analyzed within a larger continental-scale context, these five ethnic groups fall mostly outside the previously characterized Y-chromosomal gene pools of the Indo-Pakistani subcontinent. Male founder effects, coupled with culturally and topographically based constraints upon marriage and movement, are likely responsible for the high degree of genetic structure in this region.

A Phase II Study of the c-Met Inhibitor Tivantinib in Combination with FOLFOX for the Treatment of Patients with Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction, or Stomach.

BACKGROUND: This phase I/II study was designed to determine the maximum tolerated dose of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors and to evaluate the safety and efficacy of this combination for patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, or stomach. METHODS: Patients with advanced solid tumors for which FOLFOX would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design in phase I. In phase II, patients with advanced GE cancer received standard FOLFOX day 1 and tivantinib (360 mg PO BID) days 1-14 of each 2-week cycle. Restaging occurred every four cycles. The primary phase II endpoint was response rate (RR). RESULTS: Forty-nine patients were enrolled (15 on phase I and 34 on phase II). The expansion dose was established as tivantinib 360 mg BID in combination with FOLFOX. Thirty-two phase II patients were treated for a median of eight cycles (range, 1-38), with an overall RR of 38%. Treatment-related toxicities included neutropenia, fatigue, diarrhea, nausea, and peripheral neuropathy. Median progression-free survival (PFS) was 6.1 hmonths with a median time to progression of 7.0 months. Median overall survival was 9.6 months. Two patients remain on study at the time of this analysis. CONCLUSIONS: The combination treatment of tivantinib plus FOLFOX in patients with advanced GE cancer showed a response and PFS in the range of historical controls for first-line FOLFOX therapy. However, two patients had extended time on study treatment (36 and 45 cycles) at the time of data cutoff.

A Phase 2 Study of 5-Fluorouracil (5-FU), Ziv-Aflibercept, and Radiation for the Preoperative and Adjuvant Treatment of Patients with Stage II/III Rectal Cancer.

BACKGROUND: This phase II study combined aflibercept with preoperative chemoradiation for patients with stage II/III rectal cancer, followed by mFOLFOX6/aflibercept. METHODS: Patients received preoperative 5-FU (days 1-43), radiation (weeks 1-6), and aflibercept (days 1-15) each 28 day cycle for 6 weeks. Six weeks following the last aflibercept dose, patients underwent surgical resection. Four cycles of mFOLFOX6 plus aflibercept began 8 weeks after surgery. RESULTS: Common treatment-related toxicities included diarrhea, fatigue, and mucositis. The pCR rate was 23%. DISCUSSION: Afilbercept plus 5-FU-based chemoradiation was tolerated in patients with localized rectal cancer and showed a pCR rate within range of historical data.

The apportionment of tooth size and its implications in Australopithecus sediba versus other Plio-pleistocene and recent African hominins.

OBJECTIVES: Australopithecus sediba is characterized further by providing formerly unpublished and refined mesiodistal and buccolingual crown measurements in the MH1 and MH2 specimens. After size correction, these data were compared with those in other fossil and recent samples to facilitate additional insight into diachronic hominin affinities. MATERIALS AND METHODS: Six comparative samples consist of fossil species: A. africanus, A. afarensis, Homo habilis, Paranthropus robustus, P. boisei, and H. erectus. Others comprise H. sapiens and Pan troglodytes. Re-estimates of "actual" dimensions in damaged A. sediba teeth were effected through repeated measurements by independent observers. X-ray synchrotron microtomography allowed measurement of crowns obscured by matrix and noneruption. Tooth size apportionment analysis, an established technique for intraspecific comparisons, was then applied at this interspecific level to assess phenetic affinities using both within- and among-group data. RESULTS: Comparison of these highly heritable dimensions identified a general trend for smaller posterior relative to larger anterior teeth (not including canines), contra Paranthropus, that allies A. sediba with other australopiths and Homo; however, specific reductions and/or shape variation in the species' canines, third premolars, and anterior molars relative to the other teeth mirror the patterning characteristic of Homo. DISCUSSSION: Of all samples, including east African australopiths, A. sediba appears most like H. habilis, H. erectus and H. sapiens regarding how crown size is apportioned along the tooth rows. These findings parallel those in prior studies of dental and other skeletal data, including several that suggest A. sediba is a close relative of, if not ancestral to, Homo.

An initial investigation of dental morphology variation among three southern Naga ethnic groups of Northeast India.

OBJECTIVES: This study examines dental morphology trait prevalence among three southern Naga groups and compares them to 10 ethnic groups from other regions of South Asia to accomplish two objectives: assess the biological relationship of these Tibeto-Burman-speakers to speakers of non-Tibeto-Burman languages in other South Asian regions, and determine which traits distinguish northeast Indians from other South Asians. METHODS: Dental morphology traits were scored with the Arizona State University Dental Anthropology System. Tooth-trait combinations were evaluated for significant inter-trait correlation and intra-trait correspondence within dental fields. Comparisons were based on simple trait prevalence and with Smith's MMD. Affinities based on the former were accomplished with correspondence analysis and principal components analysis. Affinities based on the latter were undertaken with neighbor-joining cluster analysis and multidimensional scaling. RESULTS: After elimination due to inter-trait correlations and uniform prevalence, biodistances based on the remaining 17 tooth-trait combinations identify significant differences between northeast Indians and other South Asian ethnic groups due to high frequencies of shoveling on the maxillary incisors and Cusp 6 on the mandibular molars coupled with low frequencies of Carabelli's trait and Cusp 5 on UM1 and UM2, respectively. CONCLUSIONS: Patterns of biodistances obtained from dental morphology are consilient with those obtained from DNA indicating statistically significant differences between northeast Indians from members of ethnic groups of other regions of South Asia. Researchers should explore the sex-specific patterns. Biodistances should not be limited to "key" teeth within dental fields, for in almost every case traits present on mesial and distal teeth yield non-redundant information.

Contrasting maternal and paternal genetic histories among five ethnic groups from Khyber Pakhtunkhwa, Pakistan.

Northwest Pakistan has served as a point of entry to South Asia for different populations since ancient times. However, relatively little is known about the population genetic history of the people residing within this region. To better understand human dispersal in the region within the broader history of the subcontinent, we analyzed mtDNA diversity in 659 and Y-chromosome diversity in 678 individuals, respectively, from five ethnic groups (Gujars, Jadoons, Syeds, Tanolis and Yousafzais), from Swabi and Buner Districts, Khyber Pakhtunkhwa Province, Pakistan. The mtDNAs of all individuals were subject to control region sequencing and SNP genotyping, while Y-chromosomes were analyzed using 54 SNPs and 19 STR loci. The majority of the mtDNAs belonged to West Eurasian haplogroups, with the rest belonging to either South or East Asian lineages. Four of the five Pakistani populations (Gujars, Jadoons, Syeds, Yousafzais) possessed strong maternal genetic affinities with other Pakistani and Central Asian populations, whereas one (Tanolis) did not. Four haplogroups (R1a, R1b, O3, L) among the 11 Y-chromosome lineages observed among these five ethnic groups contributed substantially to their paternal genetic makeup. Gujars, Syeds and Yousafzais showed strong paternal genetic affinities with other Pakistani and Central Asian populations, whereas Jadoons and Tanolis had close affinities with Turkmen populations from Central Asia and ethnic groups from northeast India. We evaluate these genetic data in the context of historical and archeological evidence to test different hypotheses concerning their origins and biological relationships.

A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer.

BACKGROUND: Therapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR+) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR+/HER2- MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR+/HER2- MBC. PATIENTS AND METHODS: Patients with HR+ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%). RESULTS: Forty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures. CONCLUSION: After progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR+/HER2- MBC.

Regorafenib Prior to Selective Internal Radiation Therapy Using 90Y-Resin Microspheres for Refractory Metastatic Colorectal Cancer Liver Metastases: Analysis of Safety, Dosimetry, and Molecular Markers.

Background: This Phase II, open-label, study examined the safety of regorafenib followed by selective internal radiation therapy (SIRT) with regorafenib re-initiation in the treatment of metastatic colorectal cancer (mCRC) patients with liver metastases who are not surgical candidates. Methods: Patients received 160 mg regorafenib daily on a 21-day course followed by a 1 week washout prior to SIRT. Liver function was evaluated at 2 and 4 weeks after SIRT, and regorafenib re-initiated if liver function was normal. Patients were evaluated for safety, and restaged at weeks 6 and 12 following SIRT. In addition, protein and cytokine assays of blood were performed to identify candidate molecular biomarkers associated with outcomes. Individual patient voxel-based dosimetry assessment was performed post-SIRT. Results: Twenty-Five patients were enrolled and received a median 11 weeks regorafenib. Three patients received regorafenib, but not SIRT due to disease progression. The remaining 22 patients received SIRT with a median activity delivered to the liver of 38 mCi, mean normal liver dose of 14.98 Gy and tumor mean dose of 29.0 Gy with a tumor to normal ratio mean of 2.42. There were four treatment-related serious AEs and no treatment-related deaths. Median progression-free survival was 3.7 months and the median overall survival was 12.1 months. The relative densities of several biomolecules changed significantly during the course of treatment, most notably post-treatment increases in levels of sex-hormone binding globulin (SHBG) and decreased levels of the cytokine MIG (CXL9). Decreases in von Willebrand factor (VWF), the ankyrin repeat domain (ANKRD26), and MIG were associated with improved survival times. Post-treatment increases in alpha-2-macroglobulin (A2M) and the cytokine intercellular adhesion molecule (ICAM-1) were associated with reduced overall survival time, while increases in Eotaxin (CCL14) predicted longer overall survival times. Conclusions: The treatment of mCRC patients with liver metastases using regorafenib followed by SIRT was tolerable in this patient population. Further efficacy analysis of this treatment schema and analysis of potential molecular biomarkers using larger sample sizes is merited.

Hidden Figures: Occult Intra-Cardiac Metastases in Asymptomatic Neuroendocrine Tumor Patients.

Carcinoid heart disease is a devastating paraneoplastic consequence of unchecked hormone production from neuroendocrine tumors (NET) and often results in right-sided heart failure. While it occurs frequently in NET patients with carcinoid syndrome, cardiac metastases occur much less often and are usually only incidentally found. Gallium-68 dotatate (ga-68) is an imaging tracer which binds to somatostatin receptor 2 with greater avidity than Indium-111, the tracer used commonly in octreotide scans. Ga-68 PET/CT is the most sensitive study for detecting occult NET metastases and has emerged as the current imaging gold standard. We describe two cases from Vanderbilt University Medical Center and Stanford University Medical Center where asymptomatic patients with well-differentiated midgut NET were diagnosed with intra-cardiac metastases using ga-68 PET/CT. Management of these patients was altered based on the findings as they underwent extensive cardiac evaluation and initiation of therapy with octreotide. Fortunately, they have not suffered life-threatening cardiac complications seen in some NET patients, from other published series, such as bradycardia, heart block, syncope and arrhythmias. These possibilities suggest early cardiology evaluation and consideration of other therapies beyond octreotide, such as surgery or PRRT, may be essential for all NET patients found to have intra-cardiac metastases.

The first horse herders and the impact of early Bronze Age steppe expansions into Asia.

The Yamnaya expansions from the western steppe into Europe and Asia during the Early Bronze Age (~3000 BCE) are believed to have brought with them Indo-European languages and possibly horse husbandry. We analyzed 74 ancient whole-genome sequences from across Inner Asia and Anatolia and show that the Botai people associated with the earliest horse husbandry derived from a hunter-gatherer population deeply diverged from the Yamnaya. Our results also suggest distinct migrations bringing West Eurasian ancestry into South Asia before and after, but not at the time of, Yamnaya culture. We find no evidence of steppe ancestry in Bronze Age Anatolia from when Indo-European languages are attested there. Thus, in contrast to Europe, Early Bronze Age Yamnaya-related migrations had limited direct genetic impact in Asia.

Screening and interventions for obesity in adults: summary of the evidence for the U.S. Preventive Services Task Force.

BACKGROUND: Obesity poses a considerable and growing health burden. This review examines evidence for screening and treating obesity in adults. DATA SOURCES: MEDLINE and Cochrane Library (January 1994 through February 2003). STUDY SELECTION: Systematic reviews; randomized, controlled trials; and observational studies of obesity's health outcomes or efficacy of obesity treatment. DATA EXTRACTION: Two reviewers independently abstracted data on study design, sample, sample size, treatment, outcomes, and quality. DATA SYNTHESIS: No trials evaluated mass screening for obesity, so the authors evaluated indirect evidence for efficacy. Pharmacotherapy or counseling interventions produced modest (generally 3 to 5 kg) weight loss over at least 6 or 12 months, respectively. Counseling was most effective when intensive and combined with behavioral therapy. Maintenance strategies helped retain weight loss. Selected surgical patients lost substantial weight (10 to 159 kg over 1 to 5 years). Weight reduction improved blood pressure, lipid levels, and glucose metabolism and decreased diabetes incidence. The internal validity of the treatment trials was fair to good, and external validity was limited by the minimal ethnic or gender diversity of volunteer participants. No data evaluated counseling harms. Primary adverse drug effects included hypertension with sibutramine (mean increase, 0 mm Hg to 3.5 mm Hg) and gastrointestinal distress with orlistat (1% to 37% of patients). Fewer than 1% (pooled samples) of surgical patients died; up to 25% needed surgery again over 5 years. CONCLUSIONS: Counseling and pharmacotherapy can promote modest sustained weight loss, improving clinical outcomes. Pharmacotherapy appears safe in the short term; long-term safety has not been as strongly established. In selected patients, surgery promotes large amounts of weight loss with rare but sometimes severe complications.

Community service by North Carolina family physicians.

BACKGROUND: Community service is an integral part of American society. Although Family Medicine advocates community service through community medicine, few data exist on family physicians' involvement in voluntary community service activities or roles as community advocates. METHODS: A questionnaire was mailed to 489 North Carolina family physicians, including a 20% random sample of those in community practice and all statewide faculty physicians. The survey assessed types and amount of volunteer activity, attitudes toward volunteer work, and factors that support or inhibit participation in community service. RESULTS: The overall response rate was 54%. Most respondents reported strong interests in community service before medical school and residency, yet few reported any relevant training during medical education. More than 85% of faculty and community practice family physicians reported participating in volunteer service in the previous year (70.8 mean hours for faculty vs 45.5 mean hours for community practice; P = .06). Family physicians also reported a wide variety of lifetime volunteer activities (mean number of different faculty physician activities 20.8 vs mean number of different community practice physician activities 16.7, P = .00). Less than 50% of both physician groups reported that their practice or program publicly supports those performing community service. CONCLUSIONS: The great majority of family physicians in North Carolina regularly participate in one or more volunteer community service activities, frequently without organizational recognition. Data about the scope of service expected by communities and provided by physicians may assist the discipline in clarifying the place of volunteer community service in medical education, promotion guidelines and practice.

Horse-mounted invaders from the Russo-Kazakh steppe or agricultural colonists from western Central Asia? A craniometric investigation of the Bronze Age settlement of Xinjiang.

Numerous Bronze Age cemeteries in the oases surrounding the Täklamakan Desert of the Tarim Basin in the Xinjiang Uyghur Autonomous Region, western China, have yielded both mummified and skeletal human remains. A dearth of local antecedents, coupled with woolen textiles and the apparent Western physical appearance of the population, raised questions as to where these people came from. Two hypotheses have been offered by archaeologists to account for the origins of Bronze Age populations of the Tarim Basin. These are the "steppe hypothesis" and the "Bactrian oasis hypothesis." Eight craniometric variables from 25 Aeneolithic and Bronze Age samples, comprising 1,353 adults from the Tarim Basin, the Russo-Kazakh steppe, southern China, Central Asia, Iran, and the Indus Valley, are compared to test which, if either, of these hypotheses are supported by the pattern of phenetic affinities possessed by Bronze Age inhabitants of the Tarim Basin. Craniometric differences between samples are compared with Mahalanobis generalized distance (d2), and patterns of phenetic affinity are assessed with two types of cluster analysis (the weighted pair average linkage method and the neighbor-joining method), multidimensional scaling, and principal coordinates analysis. Results obtained by this analysis provide little support for either the steppe hypothesis or the Bactrian oasis hypothesis. Rather, the pattern of phenetic affinities manifested by Bronze Age inhabitants of the Tarim Basin suggests the presence of a population of unknown origin within the Tarim Basin during the early Bronze Age. After 1200 B.C., this population experienced significant gene flow from highland populations of the Pamirs and Ferghana Valley. These highland populations may include those who later became known as the Saka and who may have served as "middlemen" facilitating contacts between East (Tarim Basin, China) and West (Bactria, Uzbekistan) along what later became known as the Great Silk Road.