IMPORTANCE: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary ...because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). OBJECTIVE: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. DESIGN, SETTING, AND PARTICIPANTS: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. INTERVENTIONS: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. RESULTS: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 1-sided 95% CI, 0-1.16; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 95% CI, 0.62-1.17; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. CONCLUSIONS AND RELEVANCE: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003855
Four crystal structures are presented of histone deacetylase 6 (HDAC6) complexes with para-substituted phenylhydromaxamate inhibitors, including bulky peptoids. These structures provide insight ...regarding the design of capping groups that confer selectivity for binding to HDAC6, specifically with regard to interactions in a pocket formed by the L1 loop. Capping group interactions may also influence hydroxamate-Zn2+ coordination with monodentate or bidentate geometry.
Tick-borne flaviviruses (TBFV) are sustained in nature through cycling between mammalian and tick hosts. In this study, we used African green monkey kidney cells (Vero) and Ixodes scapularis tick ...cells (ISE6) to compare virus-induced changes in mammalian and arthropod cells. Using confocal microscopy, transmission electron microscopy (TEM), and electron tomography (ET), we examined viral protein distribution and the ultrastructural changes that occur during TBFV infection. Within host cells, flaviviruses cause complex rearrangement of cellular membranes for the purpose of virus replication. Virus infection was accompanied by a marked expansion in endoplasmic reticulum (ER) staining and markers for TBFV replication were localized mainly to the ER in both cell lines. TEM of Vero cells showed membrane-bound vesicles enclosed in a network of dilated, anastomosing ER cisternae. Virions were seen within the ER and were sometimes in paracrystalline arrays. Tubular structures or elongated vesicles were occasionally noted. In acutely and persistently infected ISE6 cells, membrane proliferation and vesicles were also noted; however, the extent of membrane expansion and the abundance of vesicles were lower and no viral particles were observed. Tubular profiles were far more prevalent in persistently infected ISE6 cells than in acutely infected cells. By ET, tubular profiles, in persistently infected tick cells, had a cross-sectional diameter of 60-100 nm, reached up to 800 nm in length, were closed at the ends, and were often arranged in fascicle-like bundles, shrouded with ER membrane. Our experiments provide analysis of viral protein localization within the context of both mammalian and arthropod cell lines as well as both acute and persistent arthropod cell infection. Additionally, we show for the first time 3D flavivirus infection in a vector cell line and the first ET of persistent flavivirus infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of ...substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients.
Background
Chronic migraine (CM) is a disabling disorder characterized by ≥15 headache days per month that has been shown to significantly reduce quality of life. Migraine-prevention guidelines ...recommend preventive medications as the standard of care for patients with frequent migraine. The aim of this study was to assess adherence to 14 commonly prescribed oral migraine-preventive medications (OMPMs) among patients with CM.
Methods
Retrospective claims analysis of a US claim database (Truven MarketScan® Databases) was queried to identify patients who were at least 18 years old, diagnosed with CM, and initiated an OMPM (antidepressants, beta blockers, or anticonvulsants) between January 1, 2008 and September 30, 2012. Medication possession ratios (MPR) and proportion of days covered (PDC) were calculated for each patient. A cutoff of ≥80% was used to classify adherence. The odds of adherence between OMPMs were compared using logistic regression models.
Results
Of the 75,870 patients identified with CM, 8688 met the inclusion/exclusion criteria. Adherence ranged between 26% to 29% at six months and 17% to 20% at 12 months depending on the calculation used to classify adherence (PDC and MPR, respectively). Adherence among the 14 OMPMs was similar except for amitriptyline, nortriptyline, gabapentin, and divalproex, which had significantly lower odds of adherence when compared to topiramate.
Conclusion
Adherence to OMPMs is low among the US CM population at six months and worsens by 12 months.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Migraine prevention guidelines recommend oral prophylactic medications for patients with frequent headache. This study examined oral migraine preventive medication (OMPM) treatment ...patterns by evaluating medication persistence, switching, and re-initiation in patients with chronic migraine (CM).
Methods
A retrospective US claims analysis (Truven Health MarketScan® Databases) evaluated patients ≥18 years old diagnosed with CM who had initiated an OMPM between 1 January, 2008 and 30 September, 2012. Treatment persistence was measured at six and 12 months’ follow-up. Time-to-discontinuation was assessed for each OMPM and compared using Cox regression models. Among those who discontinued, the proportion that switched OMPMs within 60 days or re-initiated treatment between 61 to 365 days, and their associated persistence rates, were also assessed.
Results
A total of 8707 patients met the inclusion/exclusion criteria. Persistence to the initial OMPM was 25% at six months and 14% at 12 months. Based on Kaplan-Meier curves, a sharp decline of patients discontinuing was observed by 30 days, and approximately half discontinued by 60 days. Similar trends in time-to-discontinuation were seen following the second or third OMPM. Amitriptyline, gabapentin, and nortriptyline had significantly higher likelihood of non-persistence compared with topiramate. Among patients who discontinued, 23% switched to another prophylactic and 41% re-initiated therapy within one year. Among patients who switched, persistence was between 10 to 13% and among re-initiated patients, persistence was between 4 to 8% at 12 months.
Conclusions
Persistence to OMPMs is poor at six months and declines further by 12 months. Switching between OMPMs is common, but results indicate that persistence worsens as patients cycle through various OMPMs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Global Temperature Change Hansen, James; Sato, Makiko; Ruedy, Reto ...
Proceedings of the National Academy of Sciences - PNAS,
09/2006, Letnik:
103, Številka:
39
Journal Article
Recenzirano
Odprti dostop
Global surface temperature has increased ≈0.2°C per decade in the past 30 years, similar to the warming rate predicted in the 1980s in initial global climate model simulations with transient ...greenhouse gas changes. Warming is larger in the Western Equatorial Pacific than in the Eastern Equatorial Pacific over the past century, and we suggest that the increased West-East temperature gradient may have increased the likelihood of strong El Niños, such as those of 1983 and 1998. Comparison of measured sea surface temperatures in the Western Pacific with paleoclimate data suggests that this critical ocean region, and probably the planet as a whole, is approximately as warm now as at the Holocene maximum and within 1°C of the maximum temperature of the past million years. We conclude that global warming of more than ≈1°C, relative to 2000, will constitute "dangerous" climate change as judged from likely effects on sea level and extermination of species.
Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and ...structure–activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.
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