FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

Memory and language risk assessment with Wada test in patients candidates for epilepsy surgery. / Evaluación de la memoria y el lenguaje mediante el test de Wada en pacientes candidatos a cirugía de epilepsia.

AIM: To determine post-surgical cognitive risk and associated factors according to lesion location in a sample of patients evaluated for epilepsy surgery with Wada test at the Fundacion Instituto Neurologico de Colombia. MATERIALS AND METHODS: An observational, retrospective, analytical study was completed in patients with drug-resistant temporal lobe epilepsy candidates for epilepsy surgery treated from 2001 to 2021, who completed the Wada test as part of the pre-surgical evaluation. A descriptive analysis of sociodemographic, clinical, imaging and neuropsychological variables was completed; a multivariate logistic regression was performed analyzing factors associated with resection risk in patients with left lesions. RESULTS A total of 369 patients were included, 54.74% of the cases were women, with a median age of seizure onset of 11 years. 92.66% of the cases had lesional epilepsy and 68.56% were secondary to hippocampal sclerosis. Left hemisphere was the most frequently affected (65.68%) being dominant for memory and language in most of the patients with a proportion of 42.82% and 81.3%, respectively. The median functional adequacy was 43.75 (IQR 0-75) and the functional reserve was 75 (IQR 25 -93.75). In 104 patients, the Wada test determined a resection risk. In patients with a left lesion, it was found that functional reserve (PRadjusted 0.99, CI 95% 0.9997-0.9998) and having a right hemispheric dominance for memory (PRadjusted 0.92, CI 95% 0.547-0.999) were protective factors for post-surgical resection risk. CONCLUSION: Wada test is a useful tool for surgical decision-making in patients with drug-resistant temporal lobe epilepsy. When considering cognitive risk, components such as memory dominance and functional reserve should be considered as protective factors for postsurgical cognitive function preservation in patients with left lesions.

TITLE: Evaluación de la memoria y el lenguaje mediante el test de Wada en pacientes candidatos a cirugía de epilepsia.Objetivo. Determinar el riesgo cognitivo posquirúrgico y factores asociados según la localización de la lesión en una muestra de pacientes evaluados para cirugía de epilepsia con el test de Wada en la Fundación Instituto Neurológico de Colombia. Materiales y métodos. Se realizó un estudio observacional, retrospectivo y analítico en pacientes con epilepsia farmacorresistente del lóbulo temporal candidatos a cirugía de epilepsia tratados entre 2001 y 2021, que completaron el test de Wada como parte de la evaluación prequirúrgica. Se realizó un análisis descriptivo de variables sociodemográficas, clínicas, imagenológicas y neuropsicológicas. Se realizó una regresión logística multivariada analizando factores asociados al riesgo de resección en pacientes con lesiones izquierdas. Resultados. Se incluyó a 369 pacientes, el 54,74% de los casos fueron mujeres, con una mediana de edad de inicio de las convulsiones de 11 años. El 92,66% de los casos presentó epilepsia lesional; de éstos, el 68,56% fue secundario a esclerosis hipocampal. El hemisferio izquierdo fue el más frecuentemente afectado (65,68%), y éste fue dominante para la memoria y el lenguaje en la mayoría de los pacientes, con una proporción del 42,82 y el 81,3%, respectivamente. La mediana de adecuación funcional fue de 43,75 (rango intercuartílico: 0-75) y la reserva funcional de 75 (rango intercuartílico: 25-93,75). En 104 pacientes, el test de Wada determinó un riesgo de resección. En pacientes con lesiones izquierdas se encontró que la reserva funcional (razón de prevalencia ajustada: 0,99; intervalo de confianza al 95%: 0,9997-0,9998) y tener dominancia del hemisferio derecho para la memoria (razón de prevalencia ajustada: 0,92; intervalo de confianza al 95%: 0,547-0,999) fueron factores asociados para determinar el riesgo de resección posquirúrgico en el test de Wada. Conclusión. El test de Wada es una herramienta útil para la toma de decisiones quirúrgicas en pacientes con epilepsia del lóbulo temporal farmacorresistente. Componentes como la dominancia de la memoria y la reserva funcional en el test de Wada deben considerarse como factores que se deben tener en cuenta en la predicción de la preservación de la función cognitiva posquirúrgica en pacientes con lesiones izquierdas.

T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers.

Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients' predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.

Regulatory implications of ctDNA in immuno-oncology for solid tumors.

In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.

Comparative study of SARS-CoV-2 infection in different cell types: Biophysical-computational approach to the role of potential receptors.

Cellular susceptibility to SARS-CoV-2 infection in the respiratory tract has been associated with the ability of the virus to interact with potential receptors on the host membrane. We have modeled viral dynamics by simulating various cellular systems and artificial conditions, including macromolecular crowding, based on experimental and transcriptomic data to infer parameters associated with viral growth and predict cell susceptibility. We have accomplished this based on the type, number and level of expression of the angiotensin-converting enzyme 2 (ACE2), transmembrane serine 2 (TMPRSS2), basigin2 (CD147), FURIN protease, neuropilin 1 (NRP1) or other less studied candidate receptors such as heat shock protein A5 (HSPA5) and angiotensin II receptor type 2 (AGTR2). In parallel, we studied the effect of simulated artificial environments on the accessibility to said proposed receptors. In addition, viral kinetic behavior dependent on the degree of cellular susceptibility was predicted. The latter was observed to be more influenced by the type of proteins and expression level, than by the number of potential proteins associated with the SARS CoV-2 infection. We predict a greater theoretical propensity to susceptibility in cell lines such as NTERA-2, SCLC-21H, HepG2 and Vero6, and a lower theoretical propensity in lines such as CaLu3, RT4, HEK293, A549 and U-251MG. An important relationship was observed between expression levels, protein diffusivity, and thermodynamically favorable interactions between host proteins and the viral spike, suggesting potential sites of early infection other than the lungs. This research is expected to stimulate future quantitative experiments and promote systematic investigation of the effect of crowding presented here.

FDA Approval Summary: Nivolumab in Combination with Ipilimumab for the Treatment of Unresectable Malignant Pleural Mesothelioma.

On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8-21.5] compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89; P = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.

Ex-PRESS® implant as the first surgical option in the iridocorneal endothelial syndrome.

Our purpose is to report the intermediate-term results of the Ex-PRESS® implant as the first surgical option in patients with Iridocorneal Endothelial (ICE) Syndrome. We describe two patients diagnosed from ICE syndrome with medically uncontrolled glaucoma and finally treated with an Ex-PRESS® implant, associating a cataract surgery in one of them. Three years after surgery, intraocular pressure remains stable without any additional medical antiglaucomatous treatment, with a well-located implant surrounded by a diffuse filtering bleb and no sight-threatening adverse events have been documented. In addition, no progression of the disease has been registered. This report encourage the Ex-PRESS® implant to be considered the first surgical option in this patients as it allows a permeable ostium in spite of the progressive synechial angle closure typical of the ICE syndrome.

FDA Approval Summary: Osimertinib for Adjuvant Treatment of Surgically Resected Non-Small Cell Lung Cancer, a Collaborative Project Orbis Review.

On December 18, 2020, the FDA approved osimertinib as adjuvant therapy in patients with non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations, as detected by an FDA-approved test. The approval was based on the ADAURA study, in which 682 patients with NSCLC were randomized to receive osimertinib (n = 339) or placebo (n = 343). Disease-free survival (DFS) in the overall population (stage IB-IIIA) was improved for patients who received osimertinib, with an HR of 0.20; 95% confidence interval (CI), 0.15-0.27; P < 0.0001. Median DFS was not reached for the osimertinib arm compared with 27.5 months (95% CI, 22.0-35.0) for patients receiving placebo. Overall survival data were not mature at the time of the approval. This application was reviewed under FDA's Project Orbis, in collaboration with Australia Therapeutic Goods Administration, Brazil ANVISA, Health Canada, Singapore Health Sciences Authority, Switzerland Swissmedic, and the United Kingdom Medicines and Healthcare products Regulatory Agency. This is the first targeted therapy adjuvant approval for NSCLC and has practice-changing implications.

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review.

On May 26, 2020, the FDA approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n = 361) or four cycles of platinum-doublet chemotherapy (n = 358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months [95% confidence interval (CI), 13.2-16.2] compared with 10.7 months (95% CI, 9.5-12.5) for patients who received chemotherapy (HR, 0.69; 96.71% CI, 0.55-0.87; P = 0.0006). Progression-free survival and overall response rate per blinded independent central review were also statistically significant. This was the first NSCLC application reviewed under FDA's Project Orbis, in collaboration with Singapore's Health Sciences Authority, Australia's Therapeutic Goods Administration, and Health Canada. The benefit-risk analysis supports FDA's approval of nivolumab with ipilimumab and chemotherapy.

Rheological properties of ethyl cellulose-monoglyceride-candelilla wax oleogel vis-a-vis edible shortenings.

The gelation process, elasticity, and mechanical recovery after shear were studied in mixed oleogels of ethylcellulose (EC), monoglycerides (MG), and candelilla wax (CW). EC oleogels produced without MG showed grainy texture due to incomplete dissolution of crystalline fractions of raw EC in the vegetable oil (150 °C). These fractions were eliminated by dissolving the raw EC/MG mixture in ethanol, evaporating the solvent, dispersing, and dissolving the solid residue in the vegetable oil (150 °C) prior gelation. The EC polymeric network, and MG, and CW crystals had a positive interaction on the elasticity of mixed oleogels. Mixed oleogels produced under static conditions showed a 100 % of elasticity recovery after shearing, a phenomenon associated with an EC interchain hydrogen bonding mediated by hydroxyl groups of MGs. This tentatively resulted from the formation of junction zones of the type EC-[MG]n-EC. The rheological behavior of these olegels was remarkably close to that of commercial shortenings.

Long telomeres and cancer risk: the price of cellular immortality.

The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hypothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.

Structuration, elastic properties scaling, and mechanical reversibility of candelilla wax oleogels with and without emulsifiers.

The crystal network development, elastic properties scaling behavior, and mechanical reversibility of candelilla wax (CW) oleogels with and without emulsifiers were studied. Saturated monoglycerides (MG) and polyglycerol polyricinoleate (PGPR) were added at 1 or 2 times the critical micelle concentration. Although the micelles of both emulsifiers act as nucleation sites for the mixture of aliphatic acids and alcohols of CW, they did not affect the oleogel's thermodynamic stability. It was established that the crystal network of CW consists of at least two types of crystals, one rich in n-hentriacontane and other rich in aliphatic acids. Both crystals species contributed significantly to the oleogel elasticity. The elastic properties scaling behavior of CW oleogels fitted the fractal model within the weak-link regime. The setting temperature and added emulsifier modified the crystal network fractal dimension. During shearing, oleogels had massive breaking of junction zones, causing the loss of fractality in the crystal network, which in turn decreased the system's elasticity.

Munchausen by proxy syndrome mimicking childhood-onset systemic lupus erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) is a chronic inflammatory multisystem autoimmune disease that requires multiple differential diagnoses. Munchausen by proxy syndrome (MBPS) is a form of child abuse, where a caregiver intentionally creates a medical history and induces or fabricates signs or disease in a patient. To our knowledge, there is no case report of MBPS mimicking cSLE diagnosis. We reported herein a 9-year-old male patient, with a history of multiple hospitalizations due to seizures with altered levels of consciousness. The mother reported malar rash, photosensitivity, alopecia, arthralgia, arterial hypertension, macroscopic hematuria, seizure and positive antinuclear antibodies. In the other service, he was treated with intravenous methylprednisolone, prednisone and mycophenolate mofetil. At 8 years and 8 months, he was admitted to our tertiary center with history of fever and macroscopic hematuria. Laboratory examinations were normal, including negative for antinuclear antibodies, anti-double stranded DNA, anticardiolipin, anti-Ro/SSA, anti-La/SSB, anti-RNP and anti-Sm antibodies. Multiple urine cultures revealed the presence of Enterococcus faecium, Acinetobacter sp., Stenotrophomonas maltophilia and Serratia marcescens, without any association with pyuria. At 8 years and 9 months, he was readmitted at emergency room with history of severe fever, headache, vomiting, photophobia, phonophobia and dizziness. The physical examination showed agitation, confusion, ataxic gait, slurred speech, horizontal nystagmus, painful facial expressions, tachycardia and weight loss. Brain magnetic resonance angiography and cerebrospinal fluid analysis were normal. During hospitalization, he had an acute episode of epistaxis and otalgia with excoriation in the auditory canal. At that moment, the suspicion of MBPS mimicking cSLE was raised and phenytoin intoxication was confirmed (peak phenytoin concentration was 45.4 mcg/mL, therapeutic range 10-20 mcg/mL). The mother and the patient were immediately separated, and she was replaced by another legal guardian. One week later, the neurological and other signs and symptoms were completely resolved. The child was placed under paternal custody with a court order and moved to another state. After that, the mother reported phenytoin use for her child and was referred to psychiatric follow-up. In conclusion, the first case of MBPS mimicking cSLE, resulting in multiple unnecessary examinations and treatments with delayed diagnosis was reported.

The antimicrobial peptide aureocin A53 as an alternative agent for biopreservation of dairy products.

AIMS: The aim of this study was to investigate the potential of aureocin A53, a staphylococcal antimicrobial peptide, for improving food safety. METHODS AND RESULTS: The antimicrobial activity of aureocin A53 against strains of Listeria monocytogenes isolated from food was tested and the bacteriocin proved to be bactericidal and bacteriolytic against the listerial strains. Aureocin A53 was neither toxic to eukaryotic cell lines nor haemolytic against sheep erythrocytes. It also exhibited a remarkable stability during storage at different temperatures and sensitivity to both simulated gastric juice and bile salts. When the antibacterial activity of aureocin A53 (256 AU ml(-1) ) was tested in skimmed milk artificially inoculated with a L. monocytogenes strain (1·0 × 10(4)  CFU ml(-1) ) isolated from food, during storage at 4°C, the bacteriocin reduced the viable counts by 7·7-log10 units up to 7 days of incubation, when compared with the controls not treated with the bacteriocin. CONCLUSIONS: Aureocin A53 exhibited several features considered important for biopreservation and remained fully active in a food matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: Taken together, the results confirmed that aureocin A53 has potential to be used as a food preservative, representing an alternative to the use of nisin in biopreservation of dairy products.

Improvement on binding of chondroitin sulfate derivatives to midkine by increasing hydrophobicity.

The interactions between chondroitin sulfate (CS) and a wide number of proteins modulate important biological processes. Here, the binding properties to midkine and pleiotrophin of sulfated, fully protected intermediates, typically obtained in the chemical synthesis of CS oligosaccharides, were tested for the first time. Using a fluorescence polarization competition experiment, we discovered that these synthetic precursors strongly bound these two closely related cytokines involved in cancer and inflammation. The relative binding affinities of these intermediates were significantly higher than those displayed by the corresponding fully deprotected oligosaccharides, indicating that the presence of hydrophobic protecting groups strongly enhanced the binding of CS-like derivatives to midkine. These compounds offer novel opportunities for the development of potent inhibitors/activators of CS-protein interactions with potential therapeutic applications.

Phase behavior, structure and rheology of candelilla wax/fully hydrogenated soybean oil mixtures with and without vegetable oil.

Vegetable oil organogelation is one of the most promising strategies to eliminate trans fatty acids in plastic fats. Organogels prepared with edible wax are stable at refrigerator and room temperature. Some functional properties (i.e., texture) of wax organogels can be improved by adding saturated triacylglycerols. Mixtures of fully hydrogenated soybean oil (FH) and candelilla wax (CW) were studied with and without the addition of high oleic safflower oil (HOSFO). Crystallization and melting behavior, X-ray diffraction, and crystalline microstructure of the mixtures were analyzed. The elastic modulus (G'), and the structural recovery after shear of the organogels were also assessed. Mixtures without HOSFO formed solid dispersions of CW and FH crystals, where up to ~10% CW crystals were incorporated into the FH crystal lattice. The vegetable oil solutions of FH/CW mixtures crystallized from the melt, developed mixed crystal networks composed of FH crystals in the ß polymorph and CW in an orthorhombic subcell packing. As the systems crystallized in the most stable polymorph, only minor microstructural changes were shown along 28days of storage at 25°C. CW and FH crystals showed a synergistic effect on the elasticity of organogels. This was attributed to the large number FH crystals nucleated on the surface of CW crystals. The structural recovery after shear was superior for mixed organogels composed of CW platelets and grainy FH crystals compared to that of CW organogels. A recovery of up to 65.7% the G' of gels formed under static conditions was observed upon shearing.

Soluble tumour necrosis factor receptor-1 (sTNFR1) levels are positively associated with exercise intensity in athletes after strenuous off-road cycling.

AIM: Strenuous exercise can enhance plasma levels of pro- and anti-inflammatory cytokines. Increases in plasma tumor necrosis factor-alpha (TNF-α) are followed rapidly by a rise in its natural inhibitors, soluble TNF receptors (sTNFRs). These inhibitors likely prevent an over-response to the cytokine. Aims of the present study were: 1) analyze plasma sTNFR1 at different time-points in response to a strenuous off-road cycling competition; 2) evaluate whether plasma levels of sTNFR1 correlate to increased blood lactate levels on completion of the exercise. METHODS: Eight trained off-road cyclists took part in this study and the data collection occurred during an official off-road race. Blood samples were collected pre-race, immediately post-race, and 1 h, 2 h and 24 h during the recovery period, for plasma sTNFR1 and blood lactate determination. RESULTS: Increase in sTNFR1 plasma levels were observed immediately post-race, 1 h and 2 h post-race (P<0.01), returning to baseline levels at the end of the recovery period (24 h). Significant correlation between plasma levels of sTNFR1 and blood lactate concentration were observed at the end of the race (r=0.925; P<0.001). CONCLUSION: An off-road cycling race stimulated an increase in plasma sTNFR1 and this anti-inflammatory molecule was positively correlated to blood lactate concentration. This result reinforces the view that exercise intensity influences the increase in plasma anti-inflammatory molecules.

Coordination of MYH DNA glycosylase and APE1 endonuclease activities via physical interactions.

MutY homologue (MYH) is a DNA glycosylase which excises adenine paired with the oxidative lesion 7,8-dihydro-8-oxoguanine (8-oxoG, or G(o)) during base excision repair (BER). Base excision by MYH results in an apurinic/apyrimidinic (AP) site in the DNA where the DNA sugar-phosphate backbone remains intact. A key feature of MYH activity is its physical interaction and coordination with AP endonuclease I (APE1), which subsequently nicks DNA 5' to the AP site. Because AP sites are mutagenic and cytotoxic, they must be processed by APE1 immediately after the action of MYH glycosylase. Our recent reports show that the interdomain connector (IDC) of human MYH (hMYH) maintains interactions with hAPE1 and the human checkpoint clamp Rad9-Rad1-Hus1 (9-1-1) complex. In this study, we used NMR chemical shift perturbation experiments to determine hMYH-binding site on hAPE1. Chemical shift perturbations indicate that the hMYH IDC peptide binds to the DNA-binding site of hAPE1 and an additional site which is distal to the APE1 DNA-binding interface. In these two binding sites, N212 and Q137 of hAPE1 are key mediators of the MYH/APE1 interaction. Intriguingly, despite the fact that hHus1 and hAPE1 both interact with the MYH IDC, hHus1 does not compete with hAPE1 for binding to hMYH. Rather, hHus1 stabilizes the hMYH/hAPE1 complex both in vitro and in cells. This is consistent with a common theme in BER, namely that the assembly of protein-DNA complexes enhances repair by efficiently coordinating multiple enzymatic steps while simultaneously minimizing the release of harmful repair intermediates.

Removal of groundwater arsenic using a household filter with iron spikes and stainless steel.

Arsenic (As) in groundwater for domestic use poses a worldwide threat to public health, most notably in rural areas. The aims of this study were: first, determine groundwater composition in a mining area in central Mexico (Huautla); second, assess As exposure through human groundwater consumption and; third, develop and test a household filter to obtain drinking water for these rural communities. From the 17th century through the 1990s, mines in the area produced Ag-galena and sphalerite from volcanic rock. Groundwater flooded the mines when they were abandoned due to low silver prices. Local households now use the water to meet domestic needs. Water from the mines was found to have high As content (0.04-0.26 mg L(-1)) and Fe, Mn, Pb and Cd were also above Mexican drinking water standards and WHO guidelines. All the population in the Huautla community was exposed to the metalloid through water used in food preparation. The best As removal was obtained with a filter using oxidized commercial fiber (HCl 2N as oxidant). Concentrations in the effluent were below Mexican drinking water standards (0.025 mg As L(-1) water) during the 105-day (2520 h) filter operation, with a maximum As removal efficiency of 95.4%. The household filter was simple, low-cost and may be very attractive for As removal in rural areas in developing countries.