Forest productivity recovery or collapse? Model-data integration insights on drought-induced tipping points.

More frequent and severe droughts are driving increased forest mortality around the globe. We urgently need to describe and predict how drought affects forest carbon cycling and identify thresholds of environmental stress that trigger ecosystem collapse. Quantifying the effects of drought at an ecosystem level is complex because dynamic climate-plant relationships can cause rapid and/or prolonged shifts in carbon balance. We employ the CARbon DAta MOdel fraMework (CARDAMOM) to investigate legacy effects of drought on forest carbon pools and fluxes. Our Bayesian model-data fusion approach uses tower observed meteorological forcing and carbon fluxes to determine the response and sensitivity of aboveground and belowground ecological processes associated with the 2012-2015 California drought. Our study area is a mid-montane mixed conifer forest in the Southern Sierras. CARDAMOM constrained with gross primary productivity (GPP) estimates covering 2011-2017 show a ~75% reduction in GPP, compared to negligible GPP change when constrained with 2011 only. Precipitation across 2012-2015 was 45% (474 mm) lower than the historical average and drove a cascading depletion in soil moisture and carbon pools (foliar, labile, roots, and litter). Adding 157 mm during an especially stressful year (2014, annual rainfall = 293 mm) led to a smaller depletion of water and carbon pools, steering the ecosystem away from a state of GPP tipping-point collapse to recovery. We present novel process-driven insights that demonstrate the sensitivity of GPP collapse to ecosystem foliar carbon and soil moisture states-showing that the full extent of GPP response takes several years to arise. Thus, long-term changes in soil moisture and carbon pools can provide a mechanistic link between drought and forest mortality. Our study provides an example for how key precipitation threshold ranges can influence forest productivity, making them useful for monitoring and predicting forest mortality events.

Can an introduced predator select for adaptive sex allocation?

Most species produce equal numbers of sons and daughters, and sex differences in survival after parental care do not usually affect this pattern. Temporary overproduction of the scarcer sex can be adaptive when generations overlap, the sexes differ in life-history expectations, and parents can anticipate future mating opportunities. However, an alternative strategy of maximizing the competitiveness of the more abundant sex in these circumstances remains unexplored. We develop theory showing how mothers can maximize reproductive value when future mate competition will be high by producing more sons in the advantageous early hatching positions within their broods. Our model for optimal birth order was supported by long-term data of offspring sex in a parrot facing catastrophic female mortality caused by introduced predators. Swift parrots (Lathamus discolor) suffer high female mortality due to introduced sugar gliders (Petaurus breviceps) creating fluctuating male-biased adult sex ratios. Offspring hatched early within broods fledged in better condition, and in support of our model were more likely to be male in years with higher adult female mortality. We found a highly significant rank-order correlation between observed and predicted birth sex ratios. Our study shows the potential for mothers to maximize reproductive value via strategic biases in offspring sex depending on the advantages conferred by birth order and the predictability of future mate competition. Our long-term data support the predictions and appear to suggest that sex allocation strategies may evolve surprisingly quickly when anthropogenic pressures on populations are severe.

42 W femtosecond Yb:Lu2O3 regenerative amplifier.

We report on a femtosecond high-power regenerative amplifier based on Yb:Lu2O3. Exploiting the excellent thermo-mechanical properties of this material, we were able to achieve up to 64.5 W in continuous-wave regime, limited only by the available pump power. In pulsed operation, 42 W of average output power at a repetition rate of 500 kHz with 780 fs long pulses could be demonstrated, resulting in a pulse peak power of ∼100 MW. The spectrum was centered at 1034 nm with an FWHM of 2.4 nm, potentially allowing for even shorter pulses. At the maximum output power the beam was nearly TEM00, with an M2 value of 1.2 in both axes.

Imaging characteristics associated with failure of nonoperative management in high-grade pediatric blunt renal trauma.

INTRODUCTION: Some children who sustain high-grade blunt renal injury may require operative intervention. In the present study, it was hypothesized that there are computed tomography (CT) characteristics that can identify which of these children are most likely to need operative intervention. MATERIALS AND METHODS: A retrospective review was performed of all pediatric blunt renal trauma patients at a single level-I trauma center from 1990 to 2015. Inclusion criteria were: children with American Association for the Surgery of Trauma (AAST) Grade-IV or V renal injuries, aged ≤18 years, and having available CT images with delayed cuts. The CTs were regraded according to the revised AAST grading system proposed by Buckley and McAninch in 2011. Radiographic characteristics of renal injury were correlated with the primary outcome of any operative intervention: ureteral stent, angiography, nephrectomy/renorrhaphy, and percutaneous nephrostomy/drain. RESULTS: One patient had a Grade-V injury and 26 patients had Grade-IV injuries. Nine patients (33.3%) underwent operative interventions. Patients in the operative intervention cohort were more likely to manifest a collecting system filling defect (P = 0.040) (Fig. A) and lacked ureteral opacification (P = 0.010). The CT characteristics, including percentage of devascularized parenchyma, medial contrast extravasation, intravascular contrast extravasation, perirenal hematoma distance and laceration location, were not statistically significant. Of the 21 patients who had a collecting system injury, eight (38.1%) needed ureteral stents. Renorrhaphy was necessary for one patient. Although the first operative intervention occurred at a median of hospital day 1 (range 0.5-2.5), additional operative interventions occurred from day 4-16. Thus, it is prudent to closely follow-up these patients for the first month after injury. Two patients with complex renal injuries had an accessory renal artery resulting in well-perfused upper and lower pole fragments, and were managed nonoperatively without readmission (Fig. B). CONCLUSIONS: Collecting system defects and lack of ureteral opacification were significantly associated with failure of nonoperative management. A multicenter trial is needed to confirm these findings and whether nonsignificant CT findings are associated with operative intervention. In the month after renal injury, these patients should be mindful of any changes in symptoms, and maintain a low index of suspicion for an emergency room visit. For the physician, close follow-up and appropriate counseling of these high-risk patients is advised.

Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity.

OBJECTIVE: To present a single center experience of a standardized prenatal multidisciplinary management protocol for fetal lower urinary tract obstruction (LUTO) and to propose a classification of fetal LUTO based on disease severity. METHODS: This was a retrospective cohort study of 25 consecutive fetal patients with prenatal diagnosis of primary LUTO. Fetal intervention was offered after evaluation by a multidisciplinary team. Analyses were conducted using Bayesian methodology to determine predictors of survival at 6 months postpartum. Odds ratios (ORs) with 95% credibility intervals are reported. RESULTS: Fifteen (60.0%) of the 25 patients referred for assessment survived to postnatal evaluation. Fetal vesicoamniotic shunt was placed in 14 (56.0%) patients with 12 survivors. Multivariable analysis suggested that fetal intervention (OR, 6.97 (0.88-70.16), Pr(OR > 1) = 96.7%), anhydramnios (OR, 0.12 (0.04-0.35), Pr(OR < 1) = 99.9%), favorable fetal urine analysis (OR, 3.98 (0.63-25.15), Pr(OR > 1) = 92.7%) and absence of renal cortical cysts (OR, 3.9 (0.66-24.2), Pr(OR > 1) = 93.3%) were predictors of survival. CONCLUSIONS: Fetal intervention and fetal renal function were independently associated with postnatal survival of fetuses with LUTO. A classification based on the severity of disease is proposed. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Impact of shear rate pattern on upper and lower limb conduit artery endothelial function in both spinal cord-injured and able-bodied men.

NEW FINDINGS: What is the central question of this study? This study addresses the following two central questions. (i) What is the impact of vascular deconditioning after spinal cord injury (SCI) on shear rate patterns and endothelial function? (ii) What is the impact of acutely altered shear rate on endothelial function in both SCI and able-bodied control subjects? What is the main finding and its importance? Two main findings in the present study were as follows: (i) reduced superficial femoral artery endothelial function in the SCI group; and (ii) acutely altered shear rate decreased endothelial function in both SCI and able-bodied control subjects. These findings may shed some light on future interventions taking into account these regulatory mechanisms. Spinal cord injury (SCI) induces vascular deconditioning below the level of the lesion and disrupts sympathetic innervation of blood vessels. It is unclear how these changes affect shear rate (SR) profiles and endothelial function when compared with able-bodied (AB) persons. Recent evidence suggests that periods of increased retrograde SR are associated with acute decreases in endothelial function, but is unknown how modified SR patterns influence sublesional vasculature in SCI. The present study examined the acute and chronic effects of altered SR patterns and oscillatory shear index on endothelial function via relative flow-mediated dilatation (FMD%) in both the brachial and superficial femoral arteries (BA and SFA, respectively) of eight individuals with SCI and eight matched AB control subjects. Baseline BA SR patterns and FMD% were similar between groups, while SFA anterograde SR was higher (P < 0.01) and FMD% lower (P = 0.04) in SCI versus AB subjects. Shear rate patterns were then acutely altered through the BA and SFA using a subsystolic cuff-inflation model. Bilateral FMD assessments were conducted before and after 30 min of unilateral inflation of a forearm or thigh blood pressure cuff to 75 mmHg. Cuff inflation resulted in concomitant increases in both anterograde (P < 0.05) and retrograde SR (P < 0.05), as well as acute decreases in FMD% (P < 0.05) in the BA and SFA in both groups. These results highlight that brief manipulation of SR patterns can acutely impair FMD% in conditions of both normal and altered sympathetic innervation and arterial remodelling. This information is crucial when designing strategies to combat impaired vascular function in both healthy and clinical populations.

Single-grating-mirror intracavity stretcher design for chirped pulse regenerative amplification.

We report for the first time, to the best of our knowledge, an innovative design concept for intracavity pulse stretching in a regenerative amplifier, employing a single "grating-mirror" based on a leaky-mode grating-waveguide design. The very compact and flexible layout allows for femtosecond pulses to be in principle easily stretched up to nanosecond durations. The design has been tested in a diode-pumped Yb:CALGO regenerative amplifier followed by a standard transmission grating compressor. Sub-200-fs pulses (stretched pulses ≈110 ps) with 205-µJ energy at 20-kHz repetition rate have been demonstrated. In order to prove the robustness and potential for energy scaling of leaky-mode grating-waveguide intracavity stretcher, we generated stretched pulses with energies of up to ≈700 µJ (400-ps long) at a lower repetition rate of 10 kHz. A simple model is proposed for the study of the cavity in presence of induced spatial chirp.

Is it time to rethink our management of dialysis patients undergoing elective ventral hernia repair? Analysis of the ACS NSQIP database.

PURPOSE: The number of patients on chronic dialysis is steadily increasing each year. There is little data that describes the outcomes in dialysis patients following elective ventral hernia repair, one of the most common general surgery procedures. Our objective was to compare the mortality and morbidity rates in dialysis versus nondialysis patients following elective ventral hernia repair. METHODS: We analysed the ACS NSQIP database to identify patients that underwent elective ventral hernia repair from 2005 to 2010. Univariate analysis and multivariate logistic regression was performed on all patients included. The main outcome variables were mortality and morbidity, length of hospital stay, and return to the operating room. RESULTS: Following elective ventral hernia repair, dialysis patients were more likely to die within 30 days or experience at least one morbidity. Dialysis patients were more likely to experience an infectious, pulmonary or vascular complication. Patients on dialysis also had a 2-fold greater risk of returning to the operating room within 30 days and stayed in the hospital an average of 1.3 days longer than nondialysis patients. Similar results were found after adjustment for demographics and comorbidities using multivariable logistic regression. CONCLUSION: This is one of the largest studies demonstrating the outcomes of a specific general surgery procedure in dialysis patients. Chronic dialysis prior to elective ventral hernia repair is associated with an increased risk of 30-day mortality, morbidity, and return to the operating room. Dialysis patients are susceptible to infectious, pulmonary, and vascular post-operative complications.

High pulse energy multiwatt Yb:CaAlGdO4 and Yb:CaF2 regenerative amplifiers.

We investigated and compared Yb:CaAlGdO4 and Yb:CaF2 regenerative amplifiers at repetition rates 5-10 kHz, a frequency range interesting for industrial applications requiring relatively high pulse energy. Both materials allow for pulse energies close to 1 mJ with sub-400-fs pulses. The two laser materials offer comparable performance in the pump power range investigated. The same regenerative amplifiers can be run up to 500 kHz for much faster material processing, with maximum output power of up to 9.4 W.

Novel therapeutic approaches for hepatitis C.

Chronic hepatitis C virus (HCV) infection afflicts a reported 170 million people worldwide and is often complicated by cirrhosis and hepatocellular carcinoma. Morbidity and mortality are decreased with the successful treatment of chronic HCV infection. The current standard of care in the treatment for genotype 1 chronic HCV is pegylated interferon (IFN)-alfa, termed PEG, and ribavirin (RBV) in conjunction with a protease inhibitor, either telaprevir or boceprevir, which results in 67-75% sustained viral response rates. Increased understanding of the HCV has allowed further development of new direct-acting antiviral (DAA) agents against the HCV and has also allowed the development of IFN-free oral treatment regimens. We anticipate the approval in late 2013 of the first nucleotide polymerase inhibitor regimen with RBV alone for genotypes 2/3 and in combination with a 12-week regimen of PEG+RBV for genotypes 1, 4, 5, and 6. Most of the promising new DAA regimens are discussed herein.

28-W, 217 fs solid-state Yb:CAlGdO4 regenerative amplifiers.

A new high-performance Yb:CaAlGdO(4) (Yb:CALGO) regenerative amplifier is demonstrated. Pumped by 116 W at ≈980 nm and seeded by means of a 92 fs oscillator, it generates as much as 36 W of average output power with chirped pulses, and 28 W with 217 fs compressed pulses at 500 kHz repetition rate. This corresponds to 56 µJ of pulse energy and 258 MW peak power. The compressed pulses have a time-bandwidth product of 0.69 and could be shortened further with an improved compressor setup.

Prevalence and risk of migraine headaches in adult fragile X premutation carriers.

FMR1 premutation carriers are common in the general population (1/130-260 females and 1/250-810 males) and can be affected by fragile X-associated tremor ataxia syndrome, fragile X-associated primary ovarian insufficiency, anxiety, depression, hypertension, sleep apnea, fibromyalgia, and hypothyroidism. Here we report the results of a pilot study to assess the prevalence and risk of migraine in FMR1 premutation carriers. Three hundred fifteen carriers (203 females; 112 males) and 154 controls (83 females; 71 males) were seen sequentially as part of a family study. A standardized medical history, physical examination and confirmation of diagnosis of migraine headaches were performed by a physician. The prevalence of migraine was 54.2% in female carriers (mean age/SD: 49.60/13.73) and 26.79% in male carriers (mean age/SD: 59.94/14.27). This prevalence was higher compared to female (25.3%; mean age/SD: 47.60/15.21; p = 0.0001) and male controls (15.5%; mean age/SD; 53.88/13.31; p = 0.0406) who underwent the same protocol and were confirmed to be negative for the FMR1 mutation by DNA testing. We hypothesize that the increased prevalence of migraine headaches in FMR1 premutation carriers is likely related to the mitochondrial abnormalities that have recently been reported. Screening for migraine should be considered when evaluating FMR1 premutation carriers in the future.

A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer.

BACKGROUND: This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS). RESULTS: A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm). CONCLUSIONS: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Single port access proctectomy with total mesorectal excision and intersphincteric resection with a primary transanal approach.

AIM: Minimally invasive surgery is advancing with single port access (SPA). We describe a technique for a SPA transabdominal combined with transanal approach to perform laparoscopic proctectomy with total mesorectal excision (TME) and intersphincteric resection of low rectal adenocarcinoma. METHOD: Transanal intersphincteric resection was followed by laparoscopic abdominal proctectomy with TME. An SPA device was placed at the site of the future stoma through a 2.5-cm incision. A hand-sewn side-to-end coloanal anastomosis was performed and a terminal loop ileostomy was created at the site of the SPA device. RESULTS: The procedure was performed on two healthy nonobese women who had not had previous abdominal surgery. The operating times were 195 and 210 min, and blood loss < 250 ml. The postoperative course was uneventful, with discharge on postoperative days 5 and 6. Pathological examination revealed adequate surgical margins and lymph node retrieval with an intact mesorectum. Four weeks after stoma closure, the scar in the right lower quadrant was 35 mm in one patient and 45 mm in the other, and the scar from the 5-mm port was barely visible. CONCLUSION: This preliminary experience shows that proctectomy with TME and intersphincteric resection can be safely performed using only two ports.

Review article: Drug-induced liver injury--its pathophysiology and evolving diagnostic tools.

BACKGROUND: Drug-induced liver injury (DILI) is a significant cause of morbidity and mortality accounting for at least 13% of acute liver failure cases in the US. It is the leading cause of acute liver failure among patients referred for liver transplantation and the most common reason that drugs in development do not obtain FDA approval. The incidence of DILI has been reported to be one in 10,000 to one in 100,000 patients; however, the actual incidence is probably higher due in part to the difficulty of diagnosis. AIM: To present a review of the current literature on DILI with a focus on its pathophysiology and evolving diagnostic modalities. METHODS: A PubMed literature search was conducted using the terms 'drug induced liver injury', 'pathophysiology', 'causality', 'diagnosis', 'toxicogenomics' and 'pharmacogenetics'. RESULTS: Drug-induced liver injury is an area of ongoing research. From the time it was first recognised, our understanding of the pathophysiology, its classification, diagnosis and reporting by established national networks continues to challenge and evolve. Metabonomics, pharmacogenetics, proteomics and transcriptomics are more recent areas of study that have been applied to further the understanding of DILI. CONCLUSIONS: Despite recent advances in our understanding of drug-induced liver injury, many aspects of its pathophysiology and clinical impact remain unclear. In addition, genomic-based studies are evolving concepts, which undoubtedly continue to contribute to our understanding of the underlying mechanisms of drug-induced liver injury.

Silica dust, diesel exhaust, and painting work are the significant occupational risk factors for lung cancer in nonsmoking Chinese men.

BACKGROUND: Few epidemiological studies have explored the associations between occupational exposures and lung cancer in lifelong nonsmoking men. METHODS: We obtained lifetime occupational history and other relevant information for 132 newly diagnosed lung cancer cases among nonsmoking Chinese men and 536 nonsmoking community referents. Unconditional multiple logistic regression analysis was performed to estimate the odds ratio (OR) of lung cancer for specific occupational exposures. RESULTS: Significantly increased lung cancer risk was found for nonsmoking workers occupationally exposed to silica dust (OR=2.58, 95% confidence interval (CI): 1.11, 6.01), diesel exhaust (OR=3.47, 95% CI: 1.08, 11.14), spray painting (OR=2.81, 95% CI: 1.14, 6.93), and nonspray painting work (OR=2.36, 95% CI: 1.04, 5.37). Silica dust exposure was associated with a significantly increased risk of adenocarcinoma (OR=2.91, 95% CI: 1.10, 7.68). We observed a positive gradient of all lung cancers and of adenocarcinoma with duration of employment for workers exposed to silica dust and spray painting. CONCLUSION: This study found an increased risk of lung cancer among nonsmoking Chinese men occupationally exposed to silica dust, diesel exhaust, and painting work.

Serum amyloid A is elevated in the serum of lung cancer patients with poor prognosis.

BACKGROUND: Lung cancer is known as the top cancer killer in most developed countries. However, there is currently no promising diagnostic or prognostic biomarker for lung cancer. This study aims to discover non-invasive differential markers in the serum of lung cancer patients, to determine the protein identity of the candidate biomarker(s), and to investigate any clinical implication of the biomarker(s) concerned. METHODS: Blood specimens were collected from 154 pre-operative patients with lung cancer and 35 healthy blood donors with no evidence of lung cancer. Fractionated serum samples were processed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (MS). Candidate biomarker was identified using sodium dodecyl sulphate polyacrylamide gel electrophoresis and tryptic digestion followed by tandem MS fragmentation analysis, which was subsequently validated with immunoassay. RESULTS: A differential protein with m/z 11.6 kDa was detected and identified as an isoform of human serum amyloid A (SAA). It was significantly increased by 1822% in lung cancer patients when compared with the healthy controls, which gave an area under the receiver operator characteristic curve of 0.88. In addition, the protein was also significantly elevated by 77% in lung cancer patients with survival <5 years when compared with patients with survival > or =5 years. CONCLUSION: There are several functions of the SAA protein, described in the context of inflammation, that are compatible with the mechanism of tumour invasion and metastasis. Our study not only detected increased SAA level in the serum of lung cancer patients but also identified that elevated SAA level may be a non-invasive biomarker useful for the prediction of lung cancer prognosis.

Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome.

Women with the fragile X mental retardation 1 (FMR1) premutation often have concerns about neurological and medical problems, as they become older and if their fathers experience fragile X-associated tremor/ataxia syndrome (FXTAS). We therefore determined the prevalence of these problems in 110 daughters of men with FXTAS [mean age of 44.8 years (SD 8.2)]. We compared them with 43 female controls with normal FMR1 alleles [mean age of 43.8 years (SD 8.1)] and 36 premutation carrier daughters of parents with the premutation, but without FXTAS [mean age of 43.5 years (SD 7.7)]. Overall, daughters of men with FXTAS have a higher prevalence of neurological symptoms including tremor, balance problems, memory problems, and dizziness, menopausal symptoms, and psychiatric involvement including sleep problems and anxiety when compared with non-carrier female controls. Reported balance problems and menopausal symptoms were significantly higher in daughters of men with FXTAS than in carrier daughters of parents without FXTAS, suggesting the potential influence of background gene effects. Therefore, neurological, psychological and gynecological surveillance should be warranted to better provide appropriate counseling, management and care for daughters of men with FXTAS. Biological markers of additional gene effects that predispose individuals with the premutation to FXTAS need to be developed.

A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer.

BACKGROUND: Identification of appropriate markers for predicting clinical benefit with erlotinib in non-small-cell lung cancer (NSCLC) may be able to guide patient selection for treatment. This open-label, multicentre, phase II trial aimed to identify genes with potential use as biomarkers for clinical benefit from erlotinib therapy. METHODS: Adults with stage IIIb/IV NSCLC in whom one or more chemotherapy regimen had failed were treated with erlotinib (150 mg/day). Tumour biopsies were analysed using gene expression profiling with Affymetrix GeneChip microarrays. Differentially expressed genes were verified using quantitative RT-PCR (qRT-PCR). RESULTS: A total of 264 patients were enrolled in the study. Gene expression profiles found no statistically significant differentially expressed genes between patients with and without clinical benefit. In an exploratory analysis in responding versus nonresponding patients, three genes on chromosome 7 were expressed at higher levels in the responding group [epidermal growth factor receptor (EGFR), phosphoserine phosphatase (PSPH) and Rap guanine nucleotide exchange factor 5 (RAPGEF5)]. Independent quantification using qRT-PCR validated the association between EGFR and PSPH overexpression, but not RAPGEF5 overexpression, and clinical outcome. CONCLUSIONS: This study supports the use of erlotinib as an alternative to chemotherapy for patients with relapsed advanced NSCLC. Genetic amplification of the EGFR region of chromosome 7 may be associated with response to erlotinib therapy.