Twenty five (26%) of 95 patients showed EGFR mutation-positive disease assessed by Scorpion ARMS. This 26% detection rate was lower than in the EURTAC study (58 [53%] of 109 serum samples) [4], and seemed to be insufficient for the screening test. However, although low detection rates were seen in serum samples, both studies showed high concordance (∼100%) between serum and tumor samples at baseline. Thus, we cannot make definitive conclusions regarding the utility of serum samples as EGFR mutation assessment specimens. This study indicates that early, local testing of EGFR mutation status is feasible and

can reliably identify patients with EGFR mutation-positive NSCLC. The reported PFS in this study of Japanese NSCLC patients was 11.8 months with first-line erlotinib treatment, which is comparable to PFS selleck chemicals llc outcomes seen with this agent in other EGFR mutation-positive populations, confirming that erlotinib can provide a good PFS benefit in this subgroup. Erlotinib was generally well tolerated, although 6 (of 103) patients reported ILD/ILD-like events and 5 were confirmed by an extramural committee, confirming

that ILD remains a risk with EGFR TKI treatment CH5424802 mw in Japanese patients. Continued monitoring for symptoms of ILD and prompt action on diagnosis is recommended. Despite this, the efficacy and manageable safety profile demonstrated by erlotinib in this study confirms that erlotinib should be recommended for the first-line treatment of Japanese NSCLC patients with EGFR mutation-positive disease. This trial was designed, funded by and monitored by Chugai Pharmaceuticals Ltd. Data were collected, analyzed and interpreted by Chugai with input from the authors and investigators. The initial draft of the manuscript was reviewed and commented on by all authors and by employees Aurora Kinase of Chugai.

The corresponding author was provided data from Chugai and took full responsibility for the final decision to submit the paper. K. Goto, M. Nishio, M. Maemondo, T. Seto, and T. Tamura have received lecture fees from Chugai Pharmaceutical Co. Ltd. N. Katakami has previously received payment from Chugai Pharmaceutical Co. Ltd. for writing or reviewing manuscripts. T. Fukuyama is an employee of Chugai Pharmaceutical Co. Ltd. All remaining authors have declared no conflicts of interest. The authors would like to thank all participating physicians, registered patients, the independent review committee members, and Joanna Salter from Gardiner-Caldwell Communications for medical writing assistance. Medical writing assistance was funded by Chugai Pharmaceutical Co. Ltd. “
“Lung cancer is the second most commonly diagnosed cancer among both men and women in the United States (US) and is the leading cause of cancer deaths in both genders [1]. Non-small cell lung cancer (NSCLC) constitutes 80–85% of all lung cancers [2].

8) e soggettivi, Fig. 9a-d. • Il gruppo M, che dimostra di arrivare a modellizzare il gioco scegliendo SdE socioeconomiche e poi sostenibili in base a caramelle e mosse disponibili (commenti alle fasi, Appendice B), presenta

spettri di gruppo coerenti con le condizioni competitive/collaborative delle prime due fasi (massimi in C11, 21), con l’ESS (ma più dal lato socioeconomico) nelle altre fasi. Quantitativamente ciò è legato agli spettri individuali: quelli di M1 Raf inhibitor hanno poche categorie e di alta frequenza, quelli di M2 sono più distribuiti, così che nelle medie prevale M1. Tuttavia, molte categorie massime per M1 sono medie o assenti

in M2, portando a chiedersi come ciò renda possibile la sostenibilità. Ebbene, mentre le categorie di massima frequenza per M1 sono proprie di una visione strategica (C13, 23, 35, 42), quelle per M2 mostrano una visione integrata, strategica e valoriale (C24, 43), nonché ludica (C14, 15): M1 sa trovare SdE per realizzare valori via via più sostenibili, M2 cerca valori sempre più FK506 cost sostenibili per tradurli in SdE. Conferma di ciò si ha nella 3. fase, dove non c׳è scontro ma difficoltà di M1 nel seguire M2. Nella prima mossa M1 gioca N aspettandosi che M2 giochi B per etica: la sua mossa è prima strategica, poi valoriale; M2 gioca invece N perché l׳orso non

rischia, e quindi conviene a tutti. La sostenibilità è dunque conseguenza della visione integrata: criticato da M1 di trarre guadagno dagli scrupoli ambientali (registrazione, commento 3. fase), M2 pareggia i guadagni nelle prime mosse della 4. fase, gettando le basi della collaborazione equa e solidale che salva l׳orso P-type ATPase su SdE BN-NN-BB-BB. Nel gruppo M riemergono dunque le visioni strategica e valoriale già identificate rispettivamente nei gruppi D e A della SPG, mostrando come la loro integrazione generi una sostenibilità molto stabile. I risultati delle analisi effettuate hanno fornito elementi sufficienti a rispondere alle domande di ricerca, unendo in un quadro unitario i diversi scenari di tutte le partite osservate. In entrambe le sperimentazioni (gruppo B escluso), i giocatori hanno dimostrato di costruire strategie previste dalla TdG, arrivando anche a distinguere fra SdE individuali (come “gioco N, gioco B”) e collettive (come “giochiamo NB”), necessarie queste ultime per le SdE miste collaborative.

Future cortical visual prosthesis implants will likely be universally wireless in operation, permitting full implantation, dural closure and therefore a lower infection risk that we estimate to be 1–2%. Standard infection prophylaxis will nonetheless be required, including broad-spectrum

and staphylococcus-specific antibiotics. Where symptomatic postoperative bleeding is concerned, a prevalence of 0.8% has previously been reported for the general neurosurgical population (Kalfas and Little, 1988), which is consistent with the figure of 1.1% reported by Fenoy and Simpson (2014) for intracerebral hemorrhage resulting from Selleckchem ERK inhibitor DBS lead insertion. However, comparing the likely risk of clinically significant intracerebral hemorrhage resulting from the insertion of DBS electrodes vs. cortical electrode arrays is difficult. A DBS electrode penetrates both cortical and subcortical tissue, with tissue damage localized to the penetration trajectory. Crizotinib In the case of cortical electrode arrays, a greater cortical surface area is compromised, however using tiled electrodes will permit the avoidance of large vessels. Moreover, the electrodes in a cortical prosthesis will only penetrate to 1.5–3.0 mm. We therefore consider that the figure of 1.1% reported for DBS implantation is a reasonable estimate of the likely risk of clinically significant intracerebral hemorrhage

resulting from cortical visual prosthesis implantation. There is also a

risk of extracerebral (extradural or subdural) bleeding after neurosurgical procedures. For epileptic patients undergoing implantation of subdural recording electrodes, Arya et al. (2013) reported that 3.53% of patients in their systematic Sitaxentan review required postoperative evacuation of intracranial hemorrhage, the most common being subdural. Importantly, the size of the grids in this review varied greatly; Wong et al. (2009) reported grid size as an independent risk factor for postoperative complications in subdural grid surgery, reflecting the increased risk with greater surgical exposure. The craniotomy required for a cortical visual prosthesis will be smaller than that required for large subdural grid implantations. For example, one group report plans to implant up to 650 electrodes across the dorsolateral surface of the occipital pole, covering an area approximately 3 cm in radius or approximately 7 cm2 (Srivastava et al., 2007). Our group is planning for implantation of up to 500 electrodes over an area covering approximately 9–10 cm2 (Lowery, 2013). Taking into account the relatively small craniotomy required for a cortical visual prosthesis, we estimate that the risk of symptomatic postoperative extracerebral bleeding (e.g. subdural/extradural) will be consistent with that of the general neurosurgical population.

, 2005). Vascular endothelial growth factor (VEGF), an important HIF1-α target gene and vascular permeabilizing factor (Fischer et al., 1999 and Minchenko et al., 1994) is induced by hypoxia and decreases the expression of BBB tight junction proteins (Keck et al., 1989), such as ZO-1 (Fischer et al., http://www.selleckchem.com/products/ipilimumab.html 2002 and Yeh et al., 2007) and occludin(Fischer

et al., 2002 and Luissint et al., 2012). Furthermore, VEGF induces BBB disruption and vasogenic edema (Kimura et al., 2005, Roberts and Palade, 1995, Sood et al., 2008, van Bruggen et al., 1999 and Wang and Tsirka, 2005) under ischemic stroke. Considering research into the role of ASK1 in ischemia-induced angiogenesis in vivo, ASK1 is involved in VEGF expression in ischemic tissue and promotes early angiogenesis by stimulating VEGF expression (Izumi et al., 2005). Aquaporin (AQP)-1, a family of water channels, is known as a water-selective transporting protein in cell membranes as CHIP28 (CHannel-like Integral membrane Protein of 28 kDa) (Agre et al., 1993 and Smith and Agre, 1991). In hypoxic conditions, AQP-1 expression is upregulated in human endothelial cells (Kaneko et al., 2008). AQP-1 activity is stimulated by hypertonicity and is regulated by ERK, p38, and JNK activation (Umenishi and Schrier, 2003) I-BET-762 datasheet and is associated with stress-induced endothelial cell migration (Saadoun et al., 2005). In present study,

we investigated whether ASK1 affects vascular permeability and edema formation after ischemic brain injury. We show that ASK1 inhibition is linked to the prevention of edema formation under hypoxic injury. Thus, our results suggest that ASK1 regulation might alleviate stroke-induced pathological alterations by protecting the disruption of BBB following cerebral ischemic injury. To investigate whether ASK1 inhibition alters the expression of permeability-related genes, we performed microarray analyses (Fig. 1). We sorted genes that were increased over 2-fold in the MCAO group compared with normal group, then screened for genes that were down-regulated more than 2-fold in the si-ASK1 group compared with the MCAO group. Several genes were selected, including matrix

metallopeptidase 3 (MMP3) ( Ashina et al., 2010), integrin alpha 8 (Itga8) ( Cucullo et al., Ribonuclease T1 2011 and Osada et al., 2011), cadherin 1 (Cdh1) ( Zechariah et al., 2013), gap junction protein beta 1 (Gjb3) ( Song et al., 2007), Selectin (Sele) ( Jin et al., 2010), intercellular adhesion molecule 1 (Icam1) ( An and Xue, 2009), aquaporin 8(Aqp8) ( Richard et al., 2003), aquaporin 12 (Aqp12) ( Calvanese et al., 2013) related with vascular permeability. Also, vascular endothelial growth factor A (Vegfa) ( Gong et al., 2014 and Poittevin et al., 2014), and vascular endothelial growth factor C (Vegfc) ( Foster et al., 2008 and Xu et al., 2013) which are related with vascular permeability were down-regulated in the si-ASK1 group compared with the MCAO group slightly.

Figure 11 shows a sequence of about 260 step-by-step run-up events (the extreme horizontal extent of a water tongue from some reference point) observed on 9 October 2006. The model results of wave run-up, together with the field data from 9 and 10 October are plotted in Figure 12. The thick line in the Figure indicates the range of the measured in situ wave run up, the dot is the mean run-up height based on measurements (the standard deviation is denoted here by the letter σ) and the cross shows the run-up height obtained from numerical computations.

It can be seen in Figure 12 that the model run-up heights in both cases lie within the range of values measured in situ; nevertheless, these values are slightly underestimated, especially in the first case. Bearing in mind that the conditions actually recorded (random/irregular) are represented in the model input by the representative wave parameters, namely the root-mean-square wave height Hrms learn more and the peak period Tp, compliance can be regarded as satisfactory. In the computations of sediment

BIBW2992 transport rates and the 24 h evolution of the beach face, the median grain size diameter was assumed to be d50 = 0.22 mm (with settling velocity ws = 0.028 m s− 1), in accordance with the parameters of the actual sediment sampled in the nearshore zone of the Lubiatowo site. In the modelling of morphological bed changes, water level variations were taken into account. Niclosamide The results relating to the net sediment transport rates and the bottom changes are shown in Figure 13 and Figure 14 respectively. The computed net sediment transport rates shown in Figure 13 first decrease slightly and then increase rapidly in front of the intersection of the beach face with the still water level. Landwards of this intersection,

the transport rates again decrease considerably. Figure 14 presents the results of the 24 h numerical simulation of the nearshore sea bed changes (dashed-dotted line), together with the measured initial and final bottom profiles (dashed and solid lines respectively). The theoretical curve computed for the representative wave (Hrms = 0.1 m, Tp = 7 s) reflects features of the sediment transport rates from Figure 13. The significant spatial variability of the net transport rates concentrated around the shoreline point causes local significant erosion and accumulation effects. These effects correspond qualitatively to the observed beach face evolution. The range of bottom changes caused by the representative wave spreads from 28.5 m to 37 m (see Figure 14). This is a much shorter distance than for measured random waves, for which changes were observed in the range 16 m–44 m. In order to take the above into account when comparing the model results with the measurements, the computed values (dashed-dotted line) were extended over the real area of sediment motion: the erosion and accumulation volumes were preserved.

5 mg and 1.25 mL, respectively, for HM-Jack, the cutoff hemoglobin concentrations in buffer for both tests were equivalent to 20 μg hemoglobin/g

feces. To monitor quality control within individual laboratories, the Health Promotion Administration has authorized the Taiwan Society of Laboratory Medicine to provide these laboratories with hemoglobin solutions and hemoglobin-spiked, stool-like matrix samples to test occult blood using both FITs every 6 months. Participating laboratories were required to analyze these test materials and return the findings for evaluation. Only accredited laboratories with findings that met the requirements of the International Organization for Standardization 15189 could participate in the nationwide program. A participant with a positive test was referred to one of approximately 485 hospitals Akt inhibitor for the confirmatory diagnosis with either a total colonoscopy or sigmoidoscopy plus barium enema. Details regarding size, location, and histopathology for

colonic neoplasms were recorded. The histopathology of a colorectal neoplasm was classified according to the criteria of the World Health Organization.8 Test performance was evaluated based on data from the prevalence screening. Short-term indicators included positive predictive value for cancer detection (number with cancer/total number of diagnostic endoscopies) and cancer detection SPTLC1 rate (number with cancer/tested selleck products population). The detection of advanced adenoma, which was defined as an adenoma of ≥10 mm in diameter or having a villous component or high-grade dysplasia, was included in the calculations for the above indicators. The per-person analysis was used for both the CRC (ie, an individual discovered with metachronous cancers counted as one individual with cancer) and advanced adenoma (ie, the

most advanced finding being an advanced adenoma). Short-term indicators also included the interval cancer rate (number of invasive cancers diagnosed after a negative FIT and <2 years to the next screen/total person-years at risk). To ascertain the occurrence of incident CRC, the screening database was linked with the Taiwan Cancer Registry, a nationwide program with high coverage (99%; each hospital mandated to report all cases of CRC) and high accuracy (percentage of death-certificate–only cases of <1% for CRC).9 The indicator of test sensitivity was generated from the number of interval cancers using the proportional incidence method based on age- and sex-specific incidence rates derived from the Taiwan Cancer Registry. Adjustments were also made for the variation of sojourn time during which CRC remained in the preclinical detectable phase.

, 1996); a kallikrein-like enzyme ( Giovanni-De-Simone et al., 1997); a β-galactoside binding lectin

( Giovanni-De-Simone et al., 2006) and also the expression of vascular apoptosis protein (VAP)-like metalloprotease from venom gland ( Tavares et al., 2008), but there have been no reports on the purification of PLA2 from this source. In this paper, we described the purification of the first PLA2 from the L. muta rhombeata venom. The www.selleckchem.com/products/AZD6244.html isolated protein, now named L. muta rhombeata toxin (LmrTX), was able to prolong thrombosis time in a photochemically induced arterial thrombosis in mice, induced anticoagulant activity in vitro and ex vivo and reduced platelet aggregation in the presence of ADP and thrombin. LmrTX was purified through an experimental protocol that combined gel filtration and Reverse-phase HPLC chromatographies. The protein consists of a single polypeptide chain and a molecular mass of 14277.50 Da. PLA2 from L muta rhombeata (LmrTX) shows three regions that retain a significant degree of similarity between group II PLA2, including the N-terminal region (forming the hydrophobic channel), the regions of the active site (formed by H48, D49, Y52 and D89) and binding of calcium (formed by Y27, G29, G31 and G32). The regions displaying a lower degree of amino acid homology correspond to structurally Alectinib less conserved elements, and are likely determinants of the diverse

pharmacology effects exhibited by venom PLA2s ( Arni and Ward, 1996). The LmrTX sequence returns high homology with the sequence of a phospholipase A2 present in the venom of C. durissus terrificus (crotoxin basic chain) (PA2B_CRODU Accession Number P62022) and L. muta muta (LmTX-I and LmTX-II) (PA2T1_LACMU Accession Number P0C942; PA2T2_ LACMU Accession number P0C943). It Etomidate is not surprising that LmrTX has a high degree of structural identity with LmTX-I and LmTX-II, since L. muta rhombeata and L. muta muta are closely related

subspecies. Zamudio and Greene (1997), used mitochondrial genes determinate, that these are, in fact, two subspecies closely related; especially between L. muta rhombeata and populations of L. muta muta from southern regions of its distribution (e.g. Mato Grosso, Brazil). These authors also point it out that the speciation process between this two subspecies it is a recently event (300–800 thousand years ago). Interestingly, it was found that the positively selection evolution process for the PLA2 family from venoms of Crotalinae subfamily take, at least 300 thousand years ( Gibbs and Rossiter, 2008). Therefore, the higher degree of structural identity between these proteins it is an expected phenomena. Nevertheless, LmrTX show biochemical and structural differences with LmTX-I and LmTX-II from L. muta muta ( Damico et al., 2005). As presented in our results LmrTX has a shorter retention time at similar conditions on HPLC-RP (21 min) compare with the two PLA2 isoforms (≥24 min) purified from L. muta muta.

, 1998; Jangchud & Chinnan, 1999). However, soy protein films became more resistant as the air temperature was increased up to 70 °C, when using higher RH ( Denavi et al., 2009). Here, the flour films plasticized with sorbitol exhibit larger TS values and lower E values than the films plasticized with glycerol, for all the drying conditions ( Tables 1 and 2). Tapia-Blácido et al. (2011) also verified that the flour film plasticized with sorbitol is more resistant to break and less flexible than the

film plasticized with glycerol. According to these authors, compared with sorbitol, glycerol is a more powerful plasticizer. This is because glycerol has smaller molecular mass (glycerol 92 mol g−1 and sorbitol 182 mol g−1), which makes it a more effective plasticizer for many edible films. Young’s modulus exhibits the same behavior as the TS as a function of T and RH (figure not shown). The larger YM values for films plasticized Proteasome inhibitors in cancer therapy with sorbitol are obtained at higher drying rates, so a different behavior is detected for the films plasticized with

glycerol. In the latter case, intermediate temperatures and a wide range of relative humidity give higher YM values. According to the analysis of variance (ANOVA), the linear, quadratic, and interaction parameters are statistically significant (p < 0.05). Therefore, these parameters were considered in the second-order model for the solubility (equations (12) and (13)). Because the F values were greater than LGK-974 cell line the listed values, the models can be considered predictive. For glycerol: equation(12)

S=55.99−3.07X1−3.59X12−6.41X2−9.69X22−4.35X1X2(R2=0.87) For sorbitol: equation(13) S=47.35−7.59X2+2.16X12−7.33X22+5.10X1X2(R2=0.90) The solubility (S) response surface obtained for flour films plasticized with glycerol contains a maximum region ( Fig. 4a), which does not occur for the films plasticized with sorbitol ( Fig. 4b). The maximum solubility of the flour film plasticized with glycerol can be verified at T ranging from 30 to 40 °C and RH from 45 to 60%, so intermediate drying rates yield more soluble flour films. On the other hand, the solubility of flour films plasticized with sorbitol increases almost Sirolimus in vivo in the full range of the RH when the films are dried at temperatures below 30 °C. However, at high T values (>40 °C), the solubility decreases when the RH values range from 33.8 to 40%, and from 70 to 76.2%. Thus, high drying rates as well as intermediate drying rates allow for the formation of films with low solubility. It can be assumed that these drying conditions promote hydrophobic interactions between lipid and proteins, as well as protein–protein and starch–starch interactions, with homogenous distribution of these interactions within the film matrix. All these interactions can culminate in lower solubility of the amaranth flour film.

While sites were located to survey hard substratum, pebbly sand habitats that occurred between the reefs were also recorded but not analysed as

they were not considered a designated part of the reef feature. During analysis of rocky habitats, observations were made that sessile RAS were occurring on pebbly sand, which therefore must be overlying bedrock that the species could attach to (Keough and Downes, 1982). This observation became of critical importance as fishers were seeking permission to scallop dredge sediments between the reef www.selleckchem.com/products/birinapant-tl32711.html features within the MPA. By returning to the video archive we could formally enumerate pebbly sand Reef Associated Species (RAS) assemblages, which had previously been ignored for the reef species recovery analysis, and compare them over time from 2008,

when the exclusion was enforced, to 3 years later in 2011. Here we test the hypothesis that, if protected from fishing, inter-reef pebbly sand habitats can support significantly more sessile RAS than similar habitats in areas that remain open to fishing. If pebbly sand habitats were found to support sessile RAS, this would provide evidence to broaden the definition of ‘reef’ as a feature, with consequences for how lines are drawn around such protected features in MPAs. We measured the following response variables for sessile RAS: Species Richness, Fluorouracil Overall Abundance, Assemblage Composition, and a subset of sessile RAS indicator species that were preselected (ross coral Pentapora fascialis, sea squirt Phallusia mammillata, dead man’s fingers Alcyonium digitatum, branching sponges, pink sea fans Eunicella verrucosa and hydroids ( Jackson et al., 2008)). The case study site is in Lyme Bay (Fig. 1), located on the south west coast of the UK. Lyme Bay comprises a mosaic

of rocky reefs with boulders, cobbles and mixed sediments, known to support some fragile biogenic reef species of national importance (Hiscock and Breckels, 2007 and Vanstaen and Eggleston, 2011). This study focused on pebbly sand habitats (particle size ⩽64 mm diameter (Irving, 2009)), which occurred between areas of rock, boulders and cobbles. All identifiable species were enumerated; however, only the sessile Reef Associated Species (sessile RAS = structure forming species Phospholipase D1 that are attached to the seabed and are associated with hard substratum) were analysed as it was considered that it was only the sessile RAS that could truly indicate the ‘reef’ feature. To determine whether sessile RAS can occur on pebbly sand if fishing pressure is relieved, the seabed was surveyed across Lyme Bay at the point when towed demersal trawling was excluded from the proposed MPA (2008), which is considered here as the ‘Before’ baseline data. Samples were taken inside the MPA or outside the MPA, which remained open to fishing (‘Open Controls; OC’). The survey was then repeated three years later. The design is effectively a Before After Control Impact (BACI) design (Underwood, 1994).

It was ethnographers, geographers, and ethnobotanists who recognized that human societies made significant, often purposeful impacts on their habitats in Amazonia (Anderson and Posey, 1989, Balee, 1989, Posey and Balee, 1989, Balick, 1984 and Smith, 1980). Their work was the first to make the point that the Amazon forest was in a sense a dynamic anthropic formation, not a virgin, natural one. They understood that there might have been an Amazon Anthropocene in prehistory. How has evidence of

the Amazon Anthropocene emerged through scientific research, and what are the methodological problems? Key sources on the Anthropocene in Amazonia were ethnohistoric and ethnographic accounts, which gave evidence of purposeful indigenous land management and habitat alteration,

RG7420 mw as well as glimpses Docetaxel mouse of the adverse impacts of colonization (Porro, 1994 and Oliveira, 1994), whose records of the transformation—large document archives including early photographs and narratives—have hardly been plumbed. Ethnographers were the first to show that tropical forest villages, far from ephemeral and small, were sizeable settlements that had existed for hundreds of years (e.g., Carneiro, 1960). Through ethnographers, ethnobotanists, human ecologists, and cultural geographers, indigenous people and peasants have been an important source of specific data on the cultural character of vegetation and the scope of human environmental interventions (Anderson and Posey, 1989, Balee, 1989, Balee, 1994, Balee, 2013, Goulding and Smith, 2007 and Henderson, 1995:17–20; Peters et al., 1989, Posey and Balee, 1989, Politis, 2007 and Smith et al., 2007). Most scientists rely on native people as guides to the habitats and sites, but this is not always acknowledged, and their information often not recorded or analyzed explicitly

as evidence. The ethnographic interviews and observations suggested that the groupings of dominant species in forests through much of Amazonia (Campbell et al., 1986, Macia and Meloxicam Svenning, 2005, Pitman et al., 2001 and Steege et al., 2013) are likely to be a human artifact (see Section ‘Anthropic forests’). Discoveries of large and complex prehistoric settlements and earthworks by archeologists helped refute the assumption that Amazonians had always lived in small, shifting villages by slash-and-burn horticulture. One important method has been surveys to map ancient human occupation sites and structures (Walker, 2012): transect surveys of regularly spaced test pits (e.g., Heckenberger et al., 1999); surface surveys along the rivers that attracted settlement (e.g., Roosevelt, 1980). But many ancient sites were destroyed by river action (Lathrap, 1970:84–87) or buried, so surface survey and shovel testing could not detect them.