Lancelets ('amphioxus') are the modern survivors of an ancient chordate lineage, with a fossil record dating back to the Cambrian period. Here we describe the structure and gene content of the highly ...polymorphic approximately 520-megabase genome of the Florida lancelet Branchiostoma floridae, and analyse it in the context of chordate evolution. Whole-genome comparisons illuminate the murky relationships among the three chordate groups (tunicates, lancelets and vertebrates), and allow not only reconstruction of the gene complement of the last common chordate ancestor but also partial reconstruction of its genomic organization, as well as a description of two genome-wide duplications and subsequent reorganizations in the vertebrate lineage. These genome-scale events shaped the vertebrate genome and provided additional genetic variation for exploitation during vertebrate evolution.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found ...in solid tumours to cause tumour-specific cell death.
We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200).
A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m
as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06).
ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.
•Bemcentinib is a selective orally bioavailable small molecule inhibitor of AXL.•Main toxicities of bemcentinib plus docetaxel were neutropenia and diarrhea.•Pharmacokinetics resembled those of ...bemcentinib and docetaxel monotherapy.•Disease control rate exceeded 80%.
AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC.
Escalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured.
21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7–10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes.
Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.
Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway ...activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients.
Patients with non-small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10-14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers.
Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, -0.71;
= 0.05) and tumor perfusion (K
; Spearman correlation, -0.71;
= 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, -0.73;
= 0.01) and GM-CSF (Spearman correlation, -1.00;
< 0.001), and reduction in tumor microvessel density (Spearman correlation, -0.69;
= 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of
and
mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations.
Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.
Background:
Greater trochanter decortication is frequently performed at the time of abductor tendon repair to theoretically increase healing potential. No previous studies have determined the effect ...that greater trochanter decortication has on the pullout strength of suture anchors.
Hypothesis/Purpose:
The purpose of this study is to determine whether greater trochanter decortication and bone mineral density affect suture anchor pullout strength in abductor tendon repair. The authors hypothesize that both will have a significant detrimental effect on suture anchor pullout strength.
Study Design:
Controlled laboratory study.
Methods:
Nineteen cadaveric proximal femurs with accompanying demographic data and computed tomography scans were skeletonized to expose the greater trochanter. Bone density measurements were acquired by converting Hounsfield units to T-score, based on a standardized volumetric sample in the intertrochanteric region of the femur. The gluteus medius insertion site on the lateral facet of the greater trochanter was evenly divided into 2 regions, anterior-distal and posterior-proximal, and each region was randomly assigned to receive either no decortication or 2 mm of bone decortication. A single biocomposite anchor was implanted in each region and initially tested with cyclic loading for 10 cycles at 0-50 N, 0-100 N, 0-150 N, and 0-200 N, followed by load to failure (LTF) tested at 1 mm/s. For each trial, the number of cycles endured, LTF, mechanism of failure, and stiffness were recorded.
Results:
Greater trochanters with no decortication and 2 mm of decortication survived a mean ± SD 35.1 ± 6.4 and 28.5 ± 10.6 cycles, respectively (P < .01). Load to failure for nondecorticated specimens was 206.7 ± 75.0 N versus 152.3 ± 60.2 N for decorticated specimens (P < .001). In a multivariate analysis, decortication and bone density were determinants in LTF (P < .05).
Conclusion:
Decortication and decreased bone mineral density significantly decreased the pullout strength of suture anchors in the lateral facet of the greater trochanter.
Clinical Relevance:
Bone density should be considered when determining whether to perform greater trochanter decortication in abductor tendon repairs.
Determining what caused the global Last Glaciation and last glacial termination, despite opposing orbital summer insolation signatures between the polar hemispheres, remains a puzzle of ...paleoclimatology. This problem can be addressed by comparing chronologies of glaciation from different latitudes and different climatic regimes in both hemispheres. Here, we present a 10Be surface‐exposure chronology of glacial landforms constructed during and since the local Last Glaciation in the continental environment of Central Asia in the high Mongolian Altai (49°N, 88°E). Four belts of lateral moraines document maximal phases of the former Khoton glacier at 35,440 ± 980 years ago, 23,430 ± 850 years ago, 20,780 ± 610 years ago, and 19,520 ± 550 years ago. Our chronology indicates that deglaciation from these maximal positions began as early as 18,810 ± 510 years ago, was well underway by 17,680 ± 510 years ago, and was nearly completed by 16,040 ± 490 years ago. Overall, our chronology shows that glaciation in western Mongolia overlapped with the global Last Glacial Maximum and that extensive recession from glacial‐to‐interglacial limits took place early in the last glacial termination during Heinrich Stadial 1. Khoton Nuur deglaciation led the demise of large Northern Hemisphere ice sheets and increases in radiative forcing agents by several millennia. We suggest that this rapid switch in the mode of glaciation implies the involvement of an additional climatic factor that could have produced locally rapid warming and deglaciation ∼18,800–16,000 years ago.
Plain Language Summary
Leading hypotheses for the causes of ice ages and their terminations involve important roles for ice‐sheet feedbacks and greenhouse gases in driving global glacial cycles. Mountain glacier length records afford valuable insights into past climate conditions because mountain glaciers are highly sensitive to the effects of atmospheric temperature changes. Here, we use glacial geology and surface‐exposure dating to chart the ice‐age history of a mountain glacier system located in the Mongolian Altai of Central Asia. Results from the Altai show that the ancient glacier achieved ice‐age maxima at the same time as glaciers in midlatitude Southern Alps of New Zealand on the opposite side of the world. Likewise, rapid and extensive glacier recession took place in both locations between ∼18,000 and 16,000 years ago—signaling an early and rapid termination of ice age conditions in these two bipolar midlatitude locations. The rapid climate warming that drove glacier retreat in western Mongolia led to the demise of the huge Northern Hemisphere ice sheets by several millennia and even outpaced the rise of atmospheric CO2. Any solution to the ice‐age climate puzzle must account for synchrony of glacial maxima as well as coeval rapid deglaciation in Central Asia and the Southern Hemisphere.
Key Points
10Be dating of moraines indicates at least four glacier maxima in the Mongolian Altai during the Last Glaciation
The timing of Mongolian glacier maxima overlapped with the global Last Glacial Maximum
Deglaciation began as early as ∼18.8 kyrs ago and interglacial conditions were achieved by ∼16.0 kyrs ago
We reconstructed the former ice cap of the Wind River Range, Wyoming, using a glaciological model with scaled modern temperature and precipitation inputs to examine probable climate during the local ...Last Glacial Maximum (LGM) (or Pinedale glaciation). A key result is that temperature anomalies of - 10 °C, -8.5 °C, -6.5 °C, and -5 °C must compensate respective precipitation values of 50%, 100%, 200%, and 300% that of modern in order for the maximum glacier system to attain equilibrium. In further sensitivity tests, we find that ice-cap area and volume shrink by 75% under a climate forcing 50% modern and 50% LGM. The glacier system disappears altogether in ∼100 years when subjected to sustained modern conditions. Our results are consistent with other interpretations of western U.S. LGM climate, and demonstrate that the Wind River Ice Cap could have disintegrated rapidly during the first phase of the termination. In future work we will simulate glacier-climate evolution as constrained by emerging 10Be moraine chronologies.
The anterior inferior iliac spine (AIIS) is a newly recognized etiology of extra-articular hip impingement. The purpose of this article is to describe an arthroscopic technique for AIIS decompression ...causing extra-articular hip impingement. Arthroscopic decompression of subspine impingement is a novel procedure that can be used to successfully relieve hip pain and improve hip function and range of motion cause by AIIS impingement.
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