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The preservation of plant specimens in herbaria has been carried out for centuries in efforts to study and confirm plant taxa. With the increasing collection of herbaria made available digitally, it is practical to use herbarium specimens for the automation of plant identification. They are also substantially more accessible and less expensive to obtain compared to field images. In fact, in remote and inaccessible habitats, field images of rare plant species are still immensely lacking. As a result, rare plant species identification is challenging due to the deficiency of training data. To address this problem, we investigate a cross-domain adaptation approach that allows knowledge transfer from a model learned from herbarium specimens to field images. We propose a model called Herbarium–Field Triplet Loss Network (HFTL network) to learn the mapping between herbarium and field domains. Specifically, the model is trained to maximize the embedding distance of different plant species and minimize the embedding distance of the same plant species given herbarium–field pairs. This paper presents the implementation and performance of the HFTL network to assess the herbarium–field similarity of plants. It corresponds to the cross-domain plant identification challenge in PlantCLEF 2020 and PlantCLEF 2021. Despite the lack of field images, our results show that the network can generalize and identify rare species. Our proposed HFTL network achieved a mean reciprocal rank score of 0.108 and 0.158 on the test set related to the species with few training field photographs in PlantCLEF 2020 and PlantCLEF 2021, respectively.

Recent advances in stimulated emission depletion (STED) microscopy offer an unparalleled avenue to study membrane dynamics of exo- and endocytosis, such as fusion pore opening, pore expansion, constriction, and closure, as well as the membrane transformation from flat-shaped to round-shaped vesicles in real time. Here we depict a method of using the state-of-the-art STED microscopy to image these membrane dynamics in bovine chromaffin cells. This method can potentially be applied to study other membrane structure dynamics in other cell model system.

Dynamic fusion pore opening and closure mediate exocytosis and endocytosis and determine their kinetics. Here, it is demonstrated in detail how confocal microscopy was used in combination with patch-clamp recording to detect three fusion modes in primary culture bovine adrenal chromaffin cells. The three fusion modes include 1) close-fusion (also called kiss-and-run), involving fusion pore opening and closure, 2) stay-fusion, involving fusion pore opening and maintaining the opened pore, and 3) shrink-fusion, involving shrinkage of the fusion-generated Ω-shape profile until it merges completely at the plasma membrane. To detect these fusion modes, the plasma membrane was labeled by overexpressing mNeonGreen attached with the PH domain of phospholipase C δ (PH-mNG), which binds to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) at the cytosol-facing leaflet of the plasma membrane; vesicles were loaded with the fluorescent false neurotransmitter FFN511 to detect vesicular content release; and Atto 655 was included in the bath solution to detect fusion pore closure. These three fluorescent probes were imaged simultaneously at ~20-90 ms per frame in live chromaffin cells to detect fusion pore opening, content release, fusion pore closure, and fusing vesicle size changes. The analysis method is described to distinguish three fusion modes from these fluorescence measurements. The method described here can, in principle, apply to many secretory cells beyond chromaffin cells.

Background The influence of amyloid protein-binding protein 2 (APPBP2) on lung cancer is unknown. Methods The function and mechanisms of APPBP2 were investigated in the NSCLC cell lines A549 and H1299. The ectopic expression of APPBP2, PPM1D and SPOP in NSCLS were examined in samples collected from ten pairs of human lung adenocarcinoma cancer tissues and adjacent normal lung tissues. shRNA vector was used for APPBP2 knockdown. Quantitative PCR and western blot assays quantified the mRNA and protein level of APPBP2, PPM1D, and SPOP. Cell proliferation was measured with BrdU, MTT, colony formation assays, and xenograft tumour growth experiments. Cell migration and invasion were analysed with transwell and wound healing assays. Co-Immunoprecipitation assay detected protein–protein interactions. Findings APPBP2 was upregulated in NSCLC tissues. Silencing APPBP2 in A549 and H1299 cells resulted in the inhibition of cell proliferation, migration, and invasion, enhancement of apoptosis, and a significant decrease in the expression of PPM1D and SPOP. Overexpression of PPM1D and SPOP attenuated the APPBP2-knockdown inhibition of NSCLC cells. Co-IP assay showed that PPM1D interacted with APPBP2. Interpretation The expression level of APPBP2 positively correlates with NSCLC cell proliferation, migration, and invasiveness. APPBP2 contributes to NSCLC progression through regulating the PPM1D and SPOP signalling pathway. This novel molecular mechanism, underlying NSCLC oncogenesis, suggests APPBP2 is a potential target for diagnosis and therapeutic intervention in NSCLC. Fund Key Program of Natural Science Research of Higher Education of Anhui Province (No. KJ2017A241), the National Natural Science Foundation of China (No. 81772493).

International audience; Several recent studies have proposed an automatic plant disease identification system based on deep learning. However, these approaches are generally based on learned classification models with target classes of joint host species-disease pairs that may not allow optimal use of the available information. This is because these approaches require distinguishing between similar host species or diseases, and more importantly, they have limited scalability due to the size of a network gradually increases as new classes are added, despite the fact that information on host species or diseases is already available. This constraint is all the more important as it can be difficult to collect/establish a specific list of all diseases for each host plant species in an actual application. In this paper, we address the problems by proposing a new conditional multi-task learning (CMTL) approach which allows the distribution of host species and disease characteristics learned simultaneously with a conditional link between them. This conditioning is formed in such a way that the knowledge to infer the prediction of one concept (the diseases) depends on the other concept (the host species), which corresponds to the way plant pathologists used to infer the diseases of the host species. We show that our approach can improve the performance of plant disease identification compared to the usual species-disease pair modeling in the previous studies. Meanwhile, we also compose a new dataset on plant disease identification that could serve as an important benchmark in this field

Classification of plants based on a multi-organ approach is very challenging. Although additional data provide more information that might help to disambiguate between species, the variability in shape and appearance in plant organs also raises the degree of complexity of the problem. Despite promising solutions built using deep learning enable representative features to be learned for plant images, the existing approaches focus mainly on generic features for species classification, disregarding the features representing plant organs. In fact, plants are complex living organisms sustained by a number of organ systems. In our approach, we introduce a hybrid generic-organ convolutional neural network (HGO-CNN), which takes into account both organ and generic information, combining them using a new feature fusion scheme for species classification. Next, instead of using a CNN-based method to operate on one image with a single organ, we extend our approach. We propose a new framework for plant structural learning using the recurrent neural network-based method. This novel approach supports classification based on a varying number of plant views, capturing one or more organs of a plant, by optimizing the contextual dependencies between them. We also present the qualitative results of our proposed models based on feature visualization techniques and show that the outcomes of visualizations depict our hypothesis and expectation. Finally, we show that by leveraging and combining the aforementioned techniques, our best network outperforms the state of the art on the PlantClef2015 benchmark. The source code and models are available at https://github.com/cs-chan/Deep-Plant .

Thermoelectric generators directly convert heat into electricity and offer a unique and very promising pathway for generating power. Titanium diboride, TiB2, is an ideal candidate for use as an electrode material in thermoelectric systems because of its refractory characteristic and excellent electrical conductivity. This study reports the effect of sputtering power density on microstructural, electrical and mechanical properties of TiB2 films fabricated by radio frequency magnetron sputtering. The TiB2 thin films were deposited at 500 °C with power densities of 5.1–12.7 W/cm2. As the power density increased, X-ray diffraction analysis showed a formation trend of highly crystallized hexagonal TiB2 with a (001) preferential orientation. X-ray photoelectron spectroscopy data revealed that only T–B chemical bonding states were present in the TiB2 phase. TiB2 films also exhibited a denser microstructure with a larger grain size. All three factors led to a lowering of the films' electrical resistivity. A minimum electrical resistivity of 6.5 × 10−4 Ωcm was obtained with a free-electron concentration of 1.2 × 1020 cm−3 and carrier mobility of 86.7 cm2 V−1 s−1. The hardness and elastic modulus were also found to increase with discharge power density from 19.5 to 26.6 GPa and from 165.2 to 196.8 GPa, respectively. This study demonstrated that the combination of high melting point and excellent electrical and mechanical properties makes TiB2 an ideal electrode material for thermoelectric applications.

Summary: Recent studies have revealed an essential role for embryonic cortical development in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, the genetic basis and underlying mechanisms remain unclear. Here, we generate mutant human embryonic stem cell lines (Mut hESCs) carrying an NR2F1-R112K mutation that has been identified in a patient with ASD features and investigate their neurodevelopmental alterations. Mut hESCs overproduce ventral telencephalic neuron progenitors (ventral NPCs) and underproduce dorsal NPCs, causing the imbalance of excitatory/inhibitory neurons. These alterations can be mainly attributed to the aberrantly activated Hedgehog signaling pathway. Moreover, the corresponding Nr2f1 point-mutant mice display a similar excitatory/inhibitory neuron imbalance and abnormal behaviors. Antagonizing the increased inhibitory synaptic transmission partially alleviates their behavioral deficits. Together, our results suggest that the NR2F1-dependent imbalance of excitatory/inhibitory neuron differentiation caused by the activated Hedgehog pathway is one precursor of neurodevelopmental disorders and may enlighten the therapeutic approaches. : Zhang et al. find that a NR2F1-R112K mutation promotes inhibitory neuron differentiation by activating the Hedgehog signaling pathway, and corresponding mutant mice display behavioral deficits related to neurodevelopmental disorders, including autistic spectrum disorder (ASD), which could be partially alleviated by antagonizing the inhibitory synaptic transmission. Keywords: neurodevelopmental disorders, autism spectrum disorders, excitatory neuron, inhibitory neuron, dorsal neuron progenitor cell, ventral neuron progenitor cell, E/I imbalance, Hedgehog signaling pathway, NR2F1

Summary Direct neuronal reprogramming potentially provides valuable sources for cell-based therapies. Proneural gene Ascl1 converts astrocytes into induced neuronal (iN) cells efficiently both in vitro and in vivo. However, the underlying mechanisms are largely unknown. By combining RNA sequencing and chromatin immunoprecipitation followed by high-throughput sequencing, we found that the expression of 1,501 genes was markedly changed during the early stages of Ascl1-induced astrocyte-to-neuron conversion and that the regulatory regions of 107 differentially expressed genes were directly bound by ASCL1. Among Ascl1's direct targets, Klf10 regulates the neuritogenesis of iN cells at the early stage, Myt1 and Myt1l are critical for the electrophysiological maturation of iN cells, and Neurod4 and Chd7 are required for the efficient conversion of astrocytes into neurons. Together, this study provides more insights into understanding the molecular mechanisms underlying Ascl1-mediated astrocyte-to-neuron conversion and will be of value for the application of direct neuronal reprogramming., Graphical Abstract, Highlights • RNA-seq and ChIP-seq were used to study Ascl1-induced astrocyte-to-neuron conversion • Early Klf10 regulates neuritogenesis and electrophysiological properties of iN cells • Myt1 and Myt1l are critical for the electrophysiological maturation of iN cells • Neurod4 and Chd7 are required for efficient conversion of astrocytes to neurons, Rao et al. studied molecular mechanisms underlying Ascl1-induced conversion of astrocytes to neurons. Among 107 direct targets of Ascl1, early expression of Klf10 regulates the neuritogenesis and the electrophysiological properties of induced neuronal (iN) cells, Myt1 and family member Myt1l are critical for the electrophysiological maturation of iN cells, and Neurod4 and Chd7 are required for efficient direct neuronal conversion.

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from &alpha, ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma, as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.

Glass doped TiO2 (GTO) thin films were deposited by radio frequency (RF) magnetron sputter at room temperature and annealed in a reductive atmosphere containing 90 % N2 and 10 % H2. Highly dense TiO2 ceramic mixed with glass consisting of multi-metal oxides (as a sintering aid) was used as the sputtering target. This sintering aid allows low temperature densification of TiO2 target through a liquid phase wetting mechanism, and also works as a doping resource. XRD and FESEM were carried out to characterize the microstructure of the GTO films and the results reveal that the doping of multi-metal ions enhances the crystallization and increases the grain size of TiO2 films. TEM analysis also showed that these metal ions were dissolved into TiO2 lattices. The electrical and optical properties of TiO2 thin films at different glass concentrations were evaluated and compared to the films merely doped with MoO3. The electrical resistivity of the GTO films reaches 9.1 × 10–4 Ω·cm at 2 wt% glass doping, corresponding to a carrier density of 8.9 x 1020 cm-3 and a mobility of 7.1 cm2/Vs. Meanwhile, the electrical resistivity of the TiO2 film doped with glass was found to be lower than that of MoO3-doped film. This was mainly attributed to the increase in carrier concentration by double doping effect of glass. The optical band gap of the GTO films ranged from 3.34 to 3.42 eV, which is greater than that of the un-doped TiO2 film. This blue shift of approximately 0.18 eV was due to the Burstein-Moss effect.

Serotonergic neurons project widely in the central nervous system and regulate a variety of behaviors. Obtaining induced serotonergic neurons (iSNs) iscritical for disease modeling, drug screening and cell therapy. Here, we found that a combination of transcription factors Ascl1, Nkx2.2, Gata2, Foxa2, and Lmx1b could convert postnatal astrocytes into functional serotonergic neurons. We further found that the iSNs expressed serotonergic neuron-specific markers and exhibited similar electrophysiological properties with native serotonergic neurons. More importantly, using an optogenetic stimulation protocol, we demonstrated that the iSNs could form synaptic connections with co-cultured neurons in dishes. Last, after transplanted into the mouse brain, astrocyte-derived iSNs survived, expressed appropriate molecular markers, and matured gradually in vivo. Taken together, our results showed that defined transcription factors were able to convert astrocytes into functional serotonergic neurons andthus provided an alternative option for generate sufficient numbers of a new neuronal subtype for therapeutic therapy.

Classification of plants based on a multi-organ approach is very challenging. Although additional data provides more information that might help to disambiguate between species, the variability in shape and appearance in plant organs also raises the degree of complexity of the problem. Existing approaches focus mainly on generic features for species classification, disregarding the features representing the organs. In fact, plants are complex entities sustained by a number of organ systems. In our approach, we exploit the PlantClef2015 benchmark, and introduce a hybrid generic-organ convolutional neural network (HGO-CNN), which takes into account both organ and generic information, combining them using a new feature fusion scheme for species classification. We show that our proposed method outperforms the state-of-the-art results.

Summary: Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons. Here, we show that seven transcription factors (TFs) (Ascl1, Phox2b, AP-2α, Gata3, Hand2, Nurr1, and Phox2a) are able to convert astrocytes and fibroblasts into induced NA (iNA) neurons. These iNA neurons express the genes required for the biosynthesis, release, and re-uptake of noradrenaline. Moreover, iNA neurons fire action potentials, receive synaptic inputs, and control the beating rate of co-cultured ventricular myocytes. Furthermore, iNA neurons survive and integrate into neural circuits after transplantation. Last, human fibroblasts can be converted into functional iNA neurons as well. Together, iNA neurons are generated by direct reprogramming, and they could be potentially useful for disease modeling and cell-based therapies. : Li et al. identified seven transcription factors that convert mouse astrocytes, fibroblasts, and human fibroblasts into induced noradrenergic (iNA) neurons. The iNA neurons are functional and integrate into neural circuits after transplantation. Single-cell RNA sequencing results showed that the transcriptome of iNA neurons converted from astrocytes and fibroblast are similar. Keywords: induced noradrenergic neurons, iNA neurons, direct neural reprogramming, astrocytes-to-neuron conversion, fibroblast-to-neuron conversion, transcription factors, noradrenaline release, mouse ventricular myocytes, optogenetic stimulation, cell transplantation, single-cell RNA sequencing

A unique glass composition based on GeO 2 , MoO 3 and V 2 O 5 (GMV) was designed to act as a sintering aid to enhance the densification and to adjust the dielectric constant of TiO 2 . This allows the low temperature co-fired ceramic processing (LTCC) of approximately 750 °C to be feasible with a desirable dielectric property. The effect of GMV glass concentration on the densification behavior and dielectrics properties of TiO 2 was investigated by dilatometer, x-ray diffractometer, scanning electron microscopy and transmission electron microscopy. The addition of glass not only was found to accelerate the TiO 2 phase transformation from anatase to rutile, but also to increase the densification rate and the grain size of TiO 2 . The glass additive formed a thin continuous liquid phase and rearranged TiO 2 particles into a dense microstructure at much lower temperature. The dielectric constants of TiO 2 were ranged from 28 to 45 depending on the concentration of glass additive, while the dielectric loss was decreased with the glass concentration as a result of denser TiO 2 microstructure.

This paper studies convolutional neural networks (CNN) to learn unsupervised feature representations for 44 different plant species, collected at the Royal Botanic Gardens, Kew, England. To gain intuition on the chosen features from the CNN model (opposed to a 'black box' solution), a visualisation technique based on the deconvolutional networks (DN) is utilized. It is found that venations of different order have been chosen to uniquely represent each of the plant species. Experimental results using these CNN features with different classifiers show consistency and superiority compared to the state-of-the art solutions which rely on hand-crafted features., Comment: 6 pages, 8 figures, accepted as oral presentation in ICIP2015, Qu\'ebec City, Canada

In vivo induction of non-neuronal cells into neurons by transcription factors offers potential therapeutic approaches for neural regeneration. Although generation of induced neuronal (iN) cells in vitro and in vivo has been reported, whether iN cells can be fully integrated into existing circuits remains unclear. Here we show that expression of achaete-scute complex homolog-like 1 (Ascl1) alone is sufficient to convert dorsal midbrain astrocytes of mice into functional iN cells in vitro and in vivo. Specific expression of Ascl1 in astrocytes by infection with GFAP–adeno-associated virus (AAV) vector converts astrocytes in dorsal midbrain, striatum, and somatosensory cortex of postnatal and adult mice into functional neurons in vivo. These iN cells mature progressively, exhibiting neuronal morphology and markers, action potentials, and synaptic inputs from and output to existing neurons. Thus, a single transcription factor, Ascl1, is sufficient to convert brain astrocytes into functional neurons, and GFAP–AAV is an efficient vector for generating iN cells from astrocytes in vivo.

Purpose: Current therapy for locally advanced prostate cancer is suboptimal. A treatment regimen was designed to improve systemic control by neoadjuvant targeting of hormone-sensitive and -insensitive micrometastatic disease and to improve local control by escalating the biologic effective dose to the prostate using estramustine (EMP) concurrently with radiotherapy. Patients and Methods: Eighteen patients with locally advanced prostate cancer (Stages T3/T4 or T1c/T2b/T2c with a Gleason score of ≥7 and a serum PSA >15 ng/ml) were entered onto this trial. Therapy consisted of two 21-day cycles of oral estramustine (10 mg/kg/day) in three divided doses and oral etoposide (50 mg/m 2 /day, in two divided doses), followed by concurrent estramustine (10 mg/kg/day, PO) and three-dimensional conformal radiotherapy. Results: Two patients required discontinuation of chemotherapy due to development of Grade 3 and 4 toxicity. All others completed both components of therapy per protocol guidelines. Minor toxicities included alopecia (100% of patients), anemia (69%), leukopenia (37%), thrombocytopenia (19%), and nausea (6%) but did not require dose modifications. There were no fatalities. Actuarial 3-year overall survival and disease-free survival (DFS) were 88% and 73%, respectively. Local control rate, assessed by repeated prostate biopsies at 18 months post completion of therapy, was 71%. Conclusion: The described regimen is well tolerated, and preliminary efficacy data are encouraging. The underlying concepts of early targeting of both hormone-sensitive and -insensitive micrometastatic clones, in combination with aggressive local therapy, warrant further investigation.

Planar positively-charged gold electrode surfaces were modified by consecutive adsorption of poly(styrene sulfonate), PSS, and protonated poly(allyl amine), PAH. By varying the sulphuric acid concentration in the PAH adsorption solution it was possible to obtain films with two different thicknesses. The permeability of the two types of self-assembled films was probed by studying the cyclic voltammetric response with two electroactive species in the supporting electrolyte; i.e. an anion, Fe(CN) 6 4− and a cation, Os(bipy) 3 3+ . Electrochemical impedance spectroscopy was also employed in the characterisation of the films.

The purpose of the present work is to investigate the potential of multi-frequency skin impedance as a versatile method for early detection of diabetes-related changes in the skin. The method implies application of a small sinusoidal voltage at various frequencies through the outermost layer of the skin. Skin impedance measurement is a quick and easy alternative to the expensive and slow study of skin biopsies by microscopy. However, the amount of data is overwhelming and the measurement noise is rather high and therefore multivariate data analysis is used. Different models of data transformation and data reduction for extraction of the parts of the data that correlate with patient status and other diagnostic parameters are discussed. Multivariate methods make it very easy to give a visual interpretation of the results. The results demonstrate how a regression model between skin impedance and other diagnostic data for diabetic patients and control groups can be developed into a novel diagnostic tool for the early discovery of possible complications for diabetic patients.

Purpose: Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken. Methods and Materials: Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status ≥70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up. Results: All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis ( n = 1), diverticular disease of the sigmoid colon ( n = 1), rectal polyp ( n = 1), and ulcerative colitis ( n = 1). Symptoms developed significantly more often in patients receiving 500–1000 mg than in patients receiving 1500–2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test). Conclusion: Intrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.

Clinically symptomatic late injury to the rectal wall occurs in about one third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of these structures. Based on our previous observations that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall of Copenhagen rats, the authors initiated a phase I clinical trial in 1998. Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, a Karnofsky performance status ofor =70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy (20 patients) and 73.8 Gy (9 patients). Therapy was delivered using a 4-field axial technique and 3-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 minutes before irradiation on the first 15 days of therapy. Amifostine dose was escalated, in cohorts, from 500 mg to 2,500 mg. Toxicity was evaluated using the Radiation Therapy Oncology Group late morbidity scale. All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. With a median follow-up time of 21 months, 9 patients (33%) had rectal bleeding (8 grade 1, 1 grade 2). Four patients (14%) had symptoms suggestive of radiation injury, which proved to be secondary to nonrelated processes. These included preexisting nonspecific proctitis (1 patient), diverticular disease of the sigmoid colon, rectal polyp (1 patient), and ulcerative colitis (1 patient). Symptoms developed significantly more often in patients receiving 500 to 1,000 mg than in patients receiving 1,500 to 2,500 mg amifostine (7 of 14 [50%] versus 2 of 13 [15%]; P =.0325, 1-sided chi(2) test). Intrarectal application of amifostine is feasible and well tolerated. A complete lack of systemic toxicity obviates the need for close monitoring of patients during and after administration. Rectal symptomatology after external beam radiotherapy to the pelvis cannot be assumed to reflect late radiation damage, because it often is a manifestation of an unrelated pathologic process. The preliminary efficacy data are encouraging and suggest that intrarectal administration of amifostine may reduce radiation damage. Further clinical studies are warranted.

n-field failure is still the most common problem for the radiation oncologist and there is significant room for improvement, even though newer techniques of tumor localization and sophisticated means of dose delivery could decrease marginal failures and improve tolerance. Models are evolving trying to understand the mechanisms of in-field failure. Accelerated tumor repopulation has been suggested as a cause of local failure. 1 Withers et al l suggest that the optimal treatment course should be approximately 4 weeks. We approximated that with 79.2 Gy in 4.5 weeks. Recently, experience originating in Mount Vernon Hospital 2'3 (described elsewhere in this issue) has apparently improved duration of survival and possibly local control in locally advanced bronchogenic carcinoma. That fractionation scheme uses three fractions per day separated by 6 hours, without the weekend breaks. The acute reactions are significant, and most of the treatments were given outside of the typical United States radiation oncology departmental hours of operation. Stimulated by this experience with continuous, hyperf rac t iona ted , accelerated radio therapy (CHART), 1'2 several investigators collaborated to develop a feasible program modifying CHART to practice in the United States. Our past experience using high doses of radiation, multiple treatment aids, and precision therapy in bronchogenic cancer have been disappointing. The local control rate at our institution has been 32% for patients with locally advanced bronchogenic cancer (AJC stages III and IV), with a 5-year, disease-free

This paper presents early results of a trial of a three-fractions-per-day (TID) regimen that is more convenient to schedule than the Continuous Hyperfractionated Accelerated Radiotherapy (CHART) protocol currently being tested in Europe. The treatment schedule used in the CHART regimen has been modified from 36 fractions of 1.5 Gy TID in 12 days to 72 fractions of 1.1 Gy in 24 treatment days, with all fractions delivered during normal working hours. With no weekend treatments, the entire course of radiotherapy is completed in less than 5 weeks. The doses used were determined using the L-Q model, with correction for incomplete repair between fractions and for accelerated repopulation of cancer cells. Comparison with historical controls shows statistically significant improvements both in CR rates for the primary tumor and in acute toxicity, as measured by reduced treatment interruptions. L-Q model calculations predict that, compared to the highest dose achieved in previous studies without exceeding tolerance, we are able to obtain a 12% increase in bioeffect dose to the primary tumor due to accelerating the treatment. An analysis of the potential tumoricidal effectiveness of this new treatment regimen shows that it should be better than several other accelerated fractionation schedules being tested for all values of T ot . For short T pot times, the advantage may be as much as one log cell kill, corresponding to a 10–15% potential improvement in local control.

Early detection and monitoring of Alzheimer’s Disease (AD) requires tools with unprecedented sensitivity for mapping its dynamic progression. We developed a dynamic brain atlas to store spatially complex profiles of degenerative rates and gray matter loss throughout the brain. Our goals were to (1) create detailed maps of degenerative change and (2) use high-dimensional flows [l] to compare individual patients’ dynamic maps with probabilistic loss rate data in the atlas. We further aimed to define robust measures of change in AD and controls and assess how change rates in different systems are correlated.