Acadian and Alleghenian remagnetization of the Jim Pond Formation, central western Maine, northern Appalachians

Samples were collected from ten sites of the Late Cambrian-Early Ordovician Jim Pond Formation for paleomagnetic study. Stepwise thermal demagnetization reveals three separable components of magnetization. Component I is typically removed by 350[deg]C; it is subparallel to the present day field (354[deg]/ + 76[deg] vs. 342[deg]/ + 72[deg]) at the site location (45.3[deg]N, 289.4[deg]E) and is considered to be a recent partial overprint. Component II, without tilt-correction, is a south-southeasterly and shallow direction (mean: 165[deg]/0[deg], k = 31.4, a95 = 8.6[deg]) that is removed over an intermediate temperature range (350-600[deg]C). Component III, without tilt-correction, is a northeasterly and shallow, upward direction (mean: 10[deg]/-24[deg], k = 21.5, a95 = 7.3[deg]) and is removed over the highest temperature range (480[deg] to 690[deg]C). Though not statistically significant, for Components II and III the precision parameter, k, decreases and the [alpha]95 increases when tilt-correction is applied, suggesting that both are post-folding magnetizations.Component II, without tilt correction, has a corresponding paleomagnetic pole located at 43[deg]N, 130[deg]E (dp, dm = 4.3[deg], 8.6[deg]), which falls near the Late Carboniferous segment of the Laurentian Apparent Polar Wander Path (APWP). Component III, without tilt correction, has a corresponding pole located at 32[deg]N, 98[deg]E (dp, dm = 4.7[deg], 7.8[deg]), which falls near the Lower-Middle Devonian segment of the APWP. We conclude that the Jim Pond Formation has undergone two Paleozoic remagnetization events, one in the Early to Middle Devonian and a second one in the Late Paleozoic. The ages of these remagnetizations coincide with the timing of major orogenic activity in the area i.e. the Acadian and Alleghenian, respectively. The remagnetization event associated with the Acadian pulse can be recognized in other paleomagnetic investigations in the northern Appalachians.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29457/1/0000539.pd

Avalonian proximity of the Ordovician Miramichi Terrane, northern New Brunswick, northern Appalachians: Paleomagnetic evidence for rifting and back-arc basin formation at the southern margin of Iapetus

A paleomagnetic investigation of the Middle Ordovician Tetagouche Group in northern New Brunswick was undertaken to determine the paleogeographic position of the Miramichi Terrane. Stepwise thermal demagnetization of pillow basalts reveals a high-temperature characteristic magnetization with a mean direction of D = 060[deg], I = +69[deg], k = 22, [alpha]95 = 13[deg] (tilt-corrected, N = 7 sites; 73 samples). A positive fold test and the presence of antipodal normal and reversed polarity directions indicate that this ancient direction is Ordovician in age, with a paleopole position of 52[deg]N, 352[deg]E. The corresponding paleolatitude of 53[deg]S places these volcanic rocks near the southern margin of the lapetus Ocean, at paleolatitudes similar to those revealed by Avalon for the Middle to Late Ordovician. The mafic and felsic volcanic rocks and marine sedimentary rocks of the Tetagouche and Fournier groups have been interpreted to be remnants of a rifted continental margin and a Middle Ordovician back-arc basin. Our results show that the process of rifting and back-arc basin formation occurred at the Avalonian margin of lapetus, which implies that Ordovician subduction was not restricted to the Laurentian margin, but also marks the southern margin of lapetus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30440/1/0000063.pd

Discordant Silurian paleolatitudes for central Newfoundland: New paleomagnetic evidence from the Springdale Group

Ancient remanences are retained by the Early Silurian (429 + 6/-5 Ma) mafic volcanics of the Springdale Caldera (five sites) and the overlying red beds (seven sites). Dual polarity magnetizations are obtained by thermal demagnetization of samples from the red beds, whereas single polarity directions are observed in the volcanics. High unblocking temperatures indicate hematite as the remanence carrier in both the volcanics and sediments. These high-temperature, characteristic remanences are easily isolated and pass both the tilt and conglomerate tests; they are likely to be of primary Silurian age. Characteristic declinations are predominantly northerly and northeasterly, and indicate significant structural rotations on a local scale. When the results of the red beds and the volcanics are combined they show characteristic inclinations that are shallower than those of the correlative Botwood Group (ca. 36[deg] vs. 43[deg]) but not nearly as shallow as those reported from the King George IV Lake area (0.5[deg]). Mean inclinations obtained from the Springdale red beds are, however, significantly shallower than those of the Springdale volcanics. The same difference can be seen in other previous Silurian paleomagnetic studies of central Newfoundland. We infer that an inclination error affects the red bed magnetizations of the Springdale Group, Botwood Group (Wigwam Formation) and rocks of the King George IV Lake area. Therefore, the results from Silurian red beds should not be used to determine paleolatitudes for central Newfoundland. The mean paleolatitude of the Springdale Group volcanics is 30[deg]. The mean paleolatitudes for both the Springdale volcanics and Botwood volcanics (Lawrenceton Formation) are indistinguishable within paleomagnetic error limits from the predicted paleolatitude of Newfoundland on the northeast-trending North American margin. Thus, no detectable post-Silurian displacement is shown by the volcanics of the Springdale Group with respect to cratonic North America.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30456/1/0000084.pd

Developing oncolytic viruses for clinical use: A consortium approach

The use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the other hand the viral infection will activate virus-directed immune responses, and may trigger immune responses directed against tumor cells and tumor antigens. To date, a wide variety of oncolytic viruses is being developed for use in cancer treatment. While the development of oncolytic viruses has often been initiated by researchers in academia and other public institutions, a large majority of the final product development and the testing of these products in clinical trials is industry led. As a consequence relatively few pre-clinical and clinical studies evaluated different oncolytic viruses i

An ex vivo Tissue Culture Model for the Assessment of Individualized Drug Responses in Prostate and Bladder Cancer

Urological malignancies, including prostate and bladder carcinoma, represent a major clinical problem due to the frequent occurrence of therapy resistance and the formation of incurable distant metastases. As a result, there is an urgent need for versatile and predictive disease models for the assessment of the individualized drug response in urological malignancies. Compound testing on ex vivo cultured patient-derived tumor tissues could represent a promising approach. In this study, we have optimized an ex vivo culture system of explanted human prostate and bladder tumors derived from clinical specimens and human cancer cell lines xenografted in mice. The explanted and cultured tumor slices remained viable and tissue architecture could be maintained for up to 10 days of culture. Treatment of ex vivo cultured human prostate and bladder cancer tissues with docetaxel and gemcitabine, respectively, resulted in a dose-dependent anti-tumor response. The dose-dependent decrease in tumor cells upon administration of the chemotherapeutic agents was preceded by an induction of apoptosis. The implementation and optimization of the tissue slice technology may facilitate the assessment of anti-tumor efficacies of existing and candidate pharmacological agents in the complex multicellular neoplastic tissues from prostate and bladder cancer patients. Our model represents a versatile “near-patient” tool to determine tumor-targeted and/or stroma-mediated anti-neoplastic responses, thus contributing to the field of personalized therapeutics

Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n= 466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age-and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P</p

The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis

High aldehyde dehydrogenase (ALDH) activity can be used to identify tumor-initiating and metastasis-initiating cells in various human carcinomas, including prostate cancer. To date, the functional importance of ALDH enzymes in prostate carcinogenesis, progression and metastasis has remained elusive. Previously we identified strong expression of ALDH7A1 in human prostate cancer cell lines, primary tumors and matched bone metastases. In this study, we evaluated whether ALDH7A1 is required for the acquisition of a metastatic stem/progenitor cell phenotype in human prostate cancer. Knockdown of ALDH7A1 expression resulted in a decrease of the α2hi/αvhi/CD44+ stem/progenitor cell subpopulation in the human prostate cancer cell line PC-3M-Pro4. In addition, ALDH7A1 knockdown significantly inhibited the clonogenic and migratory ability of human prostate cancer cells in vitro. Furthermore, a number of genes/factors involved in migration, invasion and metastasis were affected including transcription factors (snail, snail2, and twist) and osteopontin, an ECM molecule involved in metastasis. Knockdown of ALDH7A1 resulted in decreased intra-bone growth and inhibited experimentally induced (bone) metastasis, while intra-prostatic growth was not affected. In line with these observations, evidence is presented that TGF-β, a key player in cancer invasiveness and bone metastasis, strongly induced ALDH activity while BMP7 (an antagonist of TGF-β signaling) down-regulated ALDH activity. Our findings show, for the first time, that the ALDH7A1 enzyme is functionally involved in the formation of bone metastases and that the effect appeared dependent on the microenvironment, i.e., bone versus prostate

The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background

The predisposition of parasites acquiring artemisinin resistance still remains unclear beyond the mutations in Pfk13 gene and modulation of the unfolded protein response pathway. To explore the chain of casualty underlying artemisinin resistance, we reanalyze 773 P. falciparum isolates from TRACI-study integrating TWAS, GWAS, and eQTL analyses. We find the majority of P. falciparum parasites are transcriptomically converged within each geographic site with two broader physiological profiles across the Greater Mekong Subregion (GMS). We report 8720 SNP-expression linkages in the eastern GMS parasites and 4537 in the western. The minimal overlap between them suggests differential gene regulatory networks facilitating parasite adaptations to their unique host environments. Finally, we identify two genetic and physiological backgrounds associating with artemisinin resistance in the GMS, together with a farnesyltransferase protein and a thioredoxin-like protein which may act as vital intermediators linking the Pfk13 C580Y mutation to the prolonged parasite clearance time

Expanding the role of village malaria workers in Cambodia: Implementation and evaluation of four health education packages

Background: Early access to correct diagnosis and appropriate treatment is essential for malaria elimination, and in Cambodia this relies on village malaria workers (VMWs). Decreasing malaria transmission leave VMWs with diminished roles. Activities related to the control of other health conditions could keep these community health workers relevant. Methods: During 2022, 120 VMWs attended training at local health centres on four health education packages: 1. hygiene and sanitation; 2. disease surveillance; 3. management of mild illness; 4. vaccination and antenatal care. All training and evaluation sessions were documented through meeting minutes, and 19 focus group discussions (FGDs) were conducted among VMWs and health centre personnel. Audio-records of FGDs were transcribed and translated in English and underwent thematic analysis. Results: VMWs reported strong interest in the training and welcomed the expansion of their roles thus assuring their continued relevance. VMWs prioritized disease surveillance and management of mild illness among the available training packages because these topics were seen as most relevant. While training was considered comprehensible and important, the low literacy among VMWs was an impediment suggesting training materials need to be delivered visually. Since VMWs have limited resources, incentives could ensure that VMWs are motivated to undertake additional roles and responsibilities. Conclusions: The transformation of VMWs into community health workers with roles beyond malaria is a promising approach for sustaining health care provision in remote areas. Training needs to consider the low scientific literacy, time constraints and limited resources of VMWs

Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial

Background: Late treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether-lumefantrine could provide an efficacious treatment for multidrug-resistant infections. Methods: We conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2-65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether-lumefantrine alone (dosed according to WHO guidelines) or artemether-lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664). Findings: Between March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether-lumefantrine alone and 156 received artemether-lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92-99) of 156 patients with artemether-lumefantrine plus amodiaquine versus 146 (95%, 89-97) of 154 patients with artemether-lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2-1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether-lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether-lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14-1·40, p=0·17). Artemether-lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1-2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether-lumefantrine alone (vomiting, 12 [8%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether-lumefantrine alone versus five (3%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether-lumefantrine alone and 95 (61%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·0001. Interpretation: Artemether-lumefantrine plus amodiaquine provides an alternative to artemether-lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether-lumefantrine in malaria-endemic populations