Pearl millet, a key staple crop of the semi-arid tropics, is mostly grown in water-limited conditions, and improving its performance depends on how genotypes manage limited water resources. This study investigates whether the control of water loss under non-limiting water conditions is involved in the terminal drought tolerance of pearl millet. Two pairs of tolerant x sensitive pearl millet genotypes, PRLT 2/89-33-H77/833-2 and 863B-P2-ICMB 841-P3, and near-isogenic lines (NILs), introgressed with a terminal drought tolerance quantitative trait locus (QTL) from the donor parent PRLT 2/89-33 into H77/833-2 (NILs-QTL), were tested. Upon exposure to water deficit, transpiration began to decline at lower fractions of transpirable soil water (FTSW) in tolerant than in sensitive genotypes, and NILs-QTL followed the pattern of the tolerant parents. The transpiration rate (Tr, in g water loss cm(-2) d(-1)) under well-watered conditions was lower in tolerant than in sensitive parental genotypes, and the Tr of NILs-QTL followed the pattern of the tolerant parents. In addition, Tr measured in detached leaves (g water loss cm(-2) h(-1)) from field-grown plants of the parental lines showed lower Tr values in tolerant parents. Defoliation led to an increase in Tr that was higher in sensitive than in tolerant genotypes. The differences in Tr between genotypes was not related to the stomatal density. These results demonstrate that constitutive traits controlling leaf water loss under well-watered conditions correlate with the terminal drought tolerance of pearl millet. Such traits may lead to more water being available for grain filling under terminal drought.

Numerous studies have implicated the short arm of chromosome 8 as the site of one or more tumor suppressor genes inactivated in carcinogenesis of the prostate, colon, lung, and liver. Previously, we identified a homozygous deletion on chromosome 8p22 in a metastatic prostate cancer. To map this homozygous deletion physically, long-range restriction mapping was performed using yeast artificial chromosomes (YACs) spanning approximately 2 Mb of chromosome band 8p22. Subcloned genomic DNA and cDNA probes isolated by hybrid capture from these YACs were mapped in relation to one another, reinforcing map integrity. Mapped single-copy probes from the region were then applied to DNA isolated from a metastatic prostate cancer containing a chromosome 8p22 homozygous deletion and indicated that its deletion spans 730-970 kb. Candidate genes PRLTS (PDGF-receptor beta-like tumor suppressor) and CTSB (cathepsin B) are located outside the region of homozygous deletion. Généthon marker D8S549 is located approximately at the center of this region of homozygous deletion. Two new microsatellite polymorphisms, D8S1991 and D8S1992, also located within the region of homozygous deletion on chromosome 8p22, are described. Physical mapping places cosmid CI8-2644 telomeric to MSR (macrophage scavenger receptor), the reverse of a previously published map, altering the interpretation of published deletion studies. This work should prove helpful in the identification of candidate tumor suppressor genes in this region.

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177Lu-PSMA ligands. 68Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.

This research investigated whether subjects with Alzheimer's disease (AD) and ischaemic vascular dementia (IVD) associated with periventricular and deep white matter alterations can be dissociated on tests of declarative and procedural memory, as well as on MRI indices of white matter alterations and the size of the hippocampal formation. The California Verbal Learning Test (CVLT) and the Pursuit Rotor Learning Tests (PRLT) were used to measure declarative and procedural memory, respectively. Subjects with IVD obtained a higher score on the CVLT recognition discriminability index; however, on the PRLT total time on target, carry-over between trial blocks, and slope calculated for all test trials was low. Subjects with AD exhibited the opposite profile. MRI studies indicated that subjects with IVD had considerably greater white matter alterations, but larger hippocampal formations than subjects with AD. Higher scores on the CVLT recognition discriminability index were correlated with increased size of the body of the hippocampus and parahippocampal gyrus. By contrast, as the severity of white matter alterations increased the slope on the PRLT declined. In sum, subjects with AD and IVD can be dissociated on the basis of differing patterns of impairment on tests of declarative and procedural memory, and MRI indices of white matter alteration and the integrity of the hippocampal formation.

BACKGROUND

Pearl millet [Pennisetum glaucum (L.) R. Br.] is a widely cultivated drought- and high-temperature tolerant C4 cereal grown under dryland, rainfed and irrigated conditions in drought-prone regions of the tropics and sub-tropics of Africa, South Asia and the Americas. It is considered an orphan crop with relatively few genomic and genetic resources. This study was undertaken to increase the EST-based microsatellite marker and genetic resources for this crop to facilitate marker-assisted breeding.

RESULTS

Newly developed EST-SSR markers (99), along with previously mapped EST-SSR (17), genomic SSR (53) and STS (2) markers, were used to construct linkage maps of four F7 recombinant inbred populations (RIP) based on crosses ICMB 841-P3 × 863B-P2 (RIP A), H 77/833-2 × PRLT 2/89-33 (RIP B), 81B-P6 × ICMP 451-P8 (RIP C) and PT 732B-P2 × P1449-2-P1 (RIP D). Mapped loci numbers were greatest for RIP A (104), followed by RIP B (78), RIP C (64) and RIP D (59). Total map lengths (Haldane) were 615 cM, 690 cM, 428 cM and 276 cM, respectively. A total of 176 loci detected by 171 primer pairs were mapped among the four crosses. A consensus map of 174 loci (899 cM) detected by 169 primer pairs was constructed using MergeMap to integrate the individual linkage maps. Locus order in the consensus map was well conserved for nearly all linkage groups. Eighty-nine EST-SSR marker loci from this consensus map had significant BLAST hits (top hits with e-value ≤ 1E-10) on the genome sequences of rice, foxtail millet, sorghum, maize and Brachypodium with 35, 88, 58, 48 and 38 loci, respectively.

CONCLUSIONS

The consensus map developed in the present study contains the largest set of mapped SSRs reported to date for pearl millet, and represents a major consolidation of existing pearl millet genetic mapping information. This study increased numbers of mapped pearl millet SSR markers by >50%, filling important gaps in previously published SSR-based linkage maps for this species and will greatly facilitate SSR-based QTL mapping and applied marker-assisted selection programs.

BACKGROUND

Identification of genes underlying drought tolerance (DT) quantitative trait loci (QTLs) will facilitate understanding of molecular mechanisms of drought tolerance, and also will accelerate genetic improvement of pearl millet through marker-assisted selection. We report a map based on genes with assigned functional roles in plant adaptation to drought and other abiotic stresses and demonstrate its use in identifying candidate genes underlying a major DT-QTL.

RESULTS

Seventy five single nucleotide polymorphism (SNP) and conserved intron spanning primer (CISP) markers were developed from available expressed sequence tags (ESTs) using four genotypes, H 77/833-2, PRLT 2/89-33, ICMR 01029 and ICMR 01004, representing parents of two mapping populations. A total of 228 SNPs were obtained from 30.5 kb sequenced region resulting in a SNP frequency of 1/134 bp. The positions of major pearl millet linkage group (LG) 2 DT-QTLs (reported from crosses H 77/833-2 × PRLT 2/89-33 and 841B × 863B) were added to the present consensus function map which identified 18 genes, coding for PSI reaction center subunit III, PHYC, actin, alanine glyoxylate aminotransferase, uridylate kinase, acyl-CoA oxidase, dipeptidyl peptidase IV, MADS-box, serine/threonine protein kinase, ubiquitin conjugating enzyme, zinc finger C- × 8-C × 5-C × 3-H type, Hd3, acetyl CoA carboxylase, chlorophyll a/b binding protein, photolyase, protein phosphatase1 regulatory subunit SDS22 and two hypothetical proteins, co-mapping in this DT-QTL interval. Many of these candidate genes were found to have significant association with QTLs of grain yield, flowering time and leaf rolling under drought stress conditions.

CONCLUSIONS

We have exploited available pearl millet EST sequences to generate a mapped resource of seventy five new gene-based markers for pearl millet and demonstrated its use in identifying candidate genes underlying a major DT-QTL in this species. The reported gene-based markers represent an important resource for identification of candidate genes for other mapped abiotic stress QTLs in pearl millet. They also provide a resource for initiating association studies using candidate genes and also for comparing the structure and function of distantly related plant genomes such as other Poaceae members.

Pearl millet is an important component of food security in the semi-arid tropics and is assuming greater importance in the context of changing climate and increasing demand for highly nutritious food and feed. Molecular tools have been developed and applied for pearl millet on a limited scale. However, the existing tool kit needs to be strengthened further for its routine use in applied breeding programs. Here, we report enrichment of the pearl millet molecular linkage map by exploiting low-cost and high-throughput Diversity Arrays Technology (DArT) markers. Genomic representation from 95 diverse genotypes was used to develop a DArT array with circa 7,000 clones following PstI/BanII complexity reduction. This array was used to genotype a set of 24 diverse pearl millet inbreds and 574 polymorphic DArT markers were identified. The genetic relationships among the inbred lines as revealed by DArT genotyping were in complete agreement with the available pedigree data. Further, a mapping population of 140 F(7) Recombinant Inbred Lines (RILs) from cross H 77/833-2 × PRLT 2/89-33 was genotyped and an improved linkage map was constructed by integrating DArT and SSR marker data. This map contains 321 loci (258 DArTs and 63 SSRs) and spans 1148 cM with an average adjacent-marker interval length of 3.7 cM. The length of individual linkage groups (LGs) ranged from 78 cM (LG 3) to 370 cM (LG 2). This better-saturated map provides improved genome coverage and will be useful for genetic analyses of important quantitative traits. This DArT platform will also permit cost-effective background selection in marker-assisted backcrossing programs as well as facilitate comparative genomics and genome organization studies once DNA sequences of polymorphic DArT clones are available.

¹⁷⁷Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy using PSMA-617 and PSMA-I&T ligands (¹⁷⁷Lu-PRLT) is an emerging treatment in metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of ¹⁷⁷Lu-PRLT in earlier and later phases of mCRPC grouped by previous taxane chemotherapy. Methods: A retrospective analysis was performed on 167 patients with mCRPC who underwent ¹⁷⁷Lu-PRLT between March 2013 and December 2016. Patients were classified as either taxane chemotherapy pretreated (T-pretreated) or naïve (T-naïve) depending on whether they had received taxane-based chemotherapy prior to ¹⁷⁷Lu-PRLT. Clinical outcome for T-pretreated and T-naïve patients was assessed by overall survival (OS), radiographic progression-free survival, and prostate-specific antigen (PSA) response rate. Univariate and multivariable analyses were performed for both T-pretreated and T-naïve patients to determine predictors of outcome. Toxicity was categorized by the Common Terminology Criteria for Adverse Events (version 4.03). Results: Of the 167 patients treated with ¹⁷⁷Lu-PRLT, 83 were T-pretreated and 84 were T-naïve. At baseline, T-pretreated patients had overall poorer performance status, a higher prevalence of bone metastases, higher PSA levels, lower hemoglobin levels, higher alkaline phosphatase (ALP) levels and had received more additional therapies compared with T-naïve patients. Median OS was 10.7 mo for T-pretreated patients and 27.1 mo for T-naïve patients. Median radiographic progression-free survival was 6.0 mo for T-pretreated patients and 8.8 mo for T-naïve patients. PSA response assessment was evaluable in 132 patients and seen in 25 of 62 (40%) T-pretreated patients and 40 of 70 (57%) T-naïve patients. Significant determinates of inferior OS in multivariable analysis for T-pretreated patients were poorer performance status, lower cumulative administered activity, and lower baseline hemoglobin. Higher baseline alkaline phosphatase was the only significant determinate of inferior OS in multivariable analysis for T-naïve patients. Overall ¹⁷⁷Lu-PRLT was safe, with minimal adverse effects evident during follow-up in both T-pretreated and T-naïve patients. Conclusion:¹⁷⁷Lu-PRLT is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naïve and heavily pretreated patient cohorts.

OBJECTIVE

In hepatocarcinogenesis, both de novo and multistep pathways have been suggested, and in the latter a dysplastic nodule is the proposed precancerous lesion. But genetic changes involved in the dysplastic nodule are not well understood. In this study, we tried to determine whether allelic loss of the chromosome 8p and/or 11p could be involved in the development of the dysplastic nodule and/or hepatocellular carcinoma. Platelet-derived growth factor-receptor beta-like tumor suppressor gene (PRLTS) and deletion in liver cancer-1 tumor suppressor gene are located at 8p21.3-p22. The hepatitis B virus integration site and WT1 tumor suppressor gene are located at 11p13.

METHODS

We therefore studied loss of heterozygosity (LOH) of chromosome 8p21.3-p22 and 11p13 in 22 dysplastic nodules and 21 hepatocellular carcinomas. The samples, microdissected from paraffin-embedded tissues, were examined using a polymerase chain reaction-based LOH assay using microsatellite markers.

RESULTS

Loss of heterozygosity was detected for chromosome 8p21.3-p22 in nine (40.9%) of 22 dysplastic nodules and in eight (42.1%) of 19 hepatocellular carcinomas. D8S261, located adjacent to PRLTS, showed most frequent LOH: 28.6% in dysplastic nodule and 40.0% in hepatocellular carcinoma. Loss of heterozygosity on chromosome 11p13 was found in three (15.8%) of 19 dysplastic nodules and in six (31.6%) of 19 hepatocellular carcinomas. Loss of heterozygosity of D11S995 and D11S907 was found in 33.3% and 7.1% of dysplastic nodules, and 8.3% and 44.4% of hepatocellular carcinomas, respectively.

CONCLUSIONS

These results suggest that at least one putative tumor suppressor gene involved in the development and progression of hepatocellular carcinoma may be located on 8p21.3-p22 and 11p13. Particularly, PRLTS might be related to an early genetic event of hepatocarcinogenesis.

A mapping population of 104 F(3) lines of pearl millet, derived from a cross between two inbred lines H 77/833-2 x PRLT 2/89-33, was evaluated, as testcrosses on a common tester, for traits determining grain and stover yield in seven different field trials, distributed over 3 years and two seasons. The total genetic variation was partitioned into effects due to season (S), genotype (G), genotype x season interaction (G x S), and genotype x environment-within-season interaction [G x E(S)]. QTLs were determined for traits for their G, G x S, and G x E(S) effects, to assess the magnitude and the nature (cross over/non-crossover) of environmental interaction effects on individual QTLs. QTLs for some traits were associated with G effects only, while others were associated with the effects of both G and G x S and/or G, G x S and G x E(S) effects. The major G x S QTLs detected were for flowering time (on LG 4 and LG 6), and mapped to the same intervals as G x S QTLs for several other traits (including stover yield, harvest index, biomass yield and panicle number m(-2)). All three QTLs detected for grain yield were unaffected by G x S interaction however. All three QTLs for stover yield (mapping on LG 2, LG 4 and LG 6) and one of the three QTLs for grain yield (mapping on LG 4) were also free of QTL x E(S) interactions. The grain yield QTLs that were affected by QTL x E(S) interactions (mapping on LG 2 and LG 6), appeared to be linked to parallel QTL x E(S) interactions of the QTLs for panicle number m(-2) on (LG 2) and of QTLs for both panicle number m(-2) and harvest index (LG 6). In general, QTL x E(S) interactions were more frequently observed for component traits of grain and stover yield, than for grain or stover yield per se.

We have isolated a candidate tumor suppressor gene from a 600-kb region on chromosome 8p21.3-p22 that is commonly deleted in sporadic hepatocellular carcinomas (HCC), colorectal cancers (CRC), and non-small cell lung cancers (NSCLC). As this gene encodes a protein of 375 amino acids that bears significant sequence similarity to the extracellular (ligand-binding domain of platelet-derived growth factor receptor beta, we have designated it PRLTS (PDGF-receptor beta-like tumor suppressor). Structural rearrangement involving this gene was found in a sporadic NSCLC. In addition, somatic missense and frame-shift mutations were found in two HCCs and one CRC. These findings indicate that inactivation of the PRLTS gene may play a significant role in development of some carcinomas.

Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to ¹⁷⁷Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter ²²⁵Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients' quality-of-life. We hypothesized that when ¹⁷⁷Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity ²²⁵Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity.

We retrospectively analyzed pilot experience with 1 course of ²²⁵Ac-PSMA-617/¹⁷⁷Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to ¹⁷⁷Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and ¹⁷⁷Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%).

Median (minimum-maximum) administered activities were ²²⁵Ac-PSMA-617, 5.3 (1.5-7.9) MBq, and ¹⁷⁷Lu-PSMA-617, 6.9 (5.0-11.6) GBq. Significant responders to tandem therapy received ¹⁷⁷Lu-PSMA-617 monotherapy as maintenance (median [minimum-maximum]: 1 [0-5] cycle). After a median (minimum-maximum) 22 (14-63) weeks' follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12-26) weeks, and overall survival was 48 (4-92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20.

Our results suggest that a single course of tandem therapy with low-activity ²²⁵Ac-PSMA-617/full-activity ¹⁷⁷Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.

Several somatic genetic alterations have been described in non-small-cell lung carcinomas (NSCLC). Recurrent chromosomal deletions have suggested the presence of tumor-suppressor genes specifically involved in lung carcinogenesis. For one of these, 2 non-overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The LPL region has been extensively studied in NSCLC and other cancer types. Two genes, N33 and PRLTS, have been identified, but the small number of mutations excludes their involvement in the vast majority of tumors. In order to delineate a reliable region of deletional overlap on chromosome 8p in NSCLC, a series of 77 NSCLC was studied for 34 microsatellite polymorphisms distributed on chromosome 8p, using multiplex-PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, allelic losses on chromosome 8p were observed in 39% of cases. Measurement of DNA index showed that 62% of tumors were hyperploid; allelic losses were more frequent in hyperploid than in diploid tumors (54% vs. 14%; p < 10(-4)). Deletions of part of the short arm were observed in 7 instances. Our data allow definition of an interval of common deletion, flanked by the loci D8S511 and D8S1992, where the putative tumor-suppressor gene might be localized.

OBJECTIVE

Anorexia nervosa (AN) may be associated with impaired decision-making. Cognitive processes underlying this impairment remain unclear, mainly because previous assessments of this complex cognitive function were completed with a single test. Furthermore, clinical features such as mood status may impact this association. We aim to further explore the hypothesis of altered decision-making in AN.

METHODS

Sixty-three adult women with AN and 49 female controls completed a clinical assessment and were assessed by three tasks related to decision-making [Iowa Gambling Task (IGT), Balloon Analogue Risk Task (BART), Probabilistic Reversal Learning Task (PRLT)].

RESULTS

People with AN had poorer performance on the IGT and made less risky choices on the BART, whereas performances were not different on PRLT. Notably, AN patients with a current major depressive disorder showed similar performance to those with no current major depressive disorder.

CONCLUSIONS

These results tend to confirm an impaired decision making-process in people with AN and suggest that various cognitive processes such as inhibition to risk-taking or intolerance of uncertainty may underlie this condition Furthermore, these impairments seem unrelated to the potential co-occurent major depressive disorders.

The aim of this review is to report on the current status of prostate-specific membrane antigen (PSMA)-directed theranostics in prostate cancer (PC) patients. The value of 68Ga-PSMA-directed PET imaging as a diagnostic procedure for primary and recurrent PC as well as the role of evolving PSMA radioligand therapy (PRLT) in castration-resistant (CR)PC is assessed. The most eminent data from mostly retrospective studies currently available on theranostics of prostate cancer are discussed. The current knowledge on 68Ga-PSMA PET/CT implicates that primary staging with PET/CT is meaningful in patients with high-risk PC and that the combination with pelvic multi parametric (mp)MR (or PET/mpMR) reaches the highest impact on patient management. There may be a place for 68Ga-PSMA PET/CT in intermediate-risk PC patients as well, however, only a few data are available at the moment. In secondary staging for local recurrence, 68Ga-PSMA PET/mpMR is superior to PET/CT, whereas for distant recurrence, PET/CT has equivalent results and is faster and cheaper compared to PET/mpMR. 68Ga-PSMA PET/CT is superior to 18F / 11Choline PET/CT in primary staging as well as in secondary staging. In patients with biochemical relapse, PET/CT positivity is directly associated with prostate-specific antigen (PSA) increase and amounts to roughly 50% when PSA is raised to ≤0.5 ng/ml and to ≥90% above 1 ng/ml. Significant clinical results have so far been achieved with the subsequent use of radiolabeled PSMA ligands in the treatment of CRPC. Accumulated activities of 30 to 50 GBq of 177Lu-PSMA ligands seem to be clinically safe with biochemical response and PERCIST/RECIST response in around 75% of patients along with xerostomia in 5-10% of patients as the only notable side effect. On the basis of the current literature, we conclude that PSMA-directed theranostics do have a major clinical impact in diagnosis and therapy of PC patients. We recommend that 68Ga-PSMA PET/CT should be performed in primary staging together with pelvic mpMR in high-risk patients and in all patients for secondary staging, and that PSMA-directed therapy is a potent strategy in CRPC patients when other treatment options have failed. The combination of PSMA-directed therapy with existing therapy modalities (such as 223Ra-chloride or androgen deprivation therapy) has to be explored, and prospective clinical multicenter trials with theranostics are warranted.

Liubao tea is a type of traditional Chinese tea, belonging to the dark teas. This study is a basic research of the contained polyphenols (active substances) and detected preventive effects of polyphenols of raw Liubao tea (PRLT) on mouse gastric injuries induced by HCl/ethanol. High-pressure liquid chromatography was used to analyze the components of PRLT. Furthermore, a mouse gastric injury model was established to observe the preventive effects. PRLT was shown to contain gallic acid, EGC (epigallocatechin), catechin, caffeine, EC (epicatechin), EGCG (epigallocatechin gallate), GCG (gallocatechin gallate), and ECG (epicatechin gallate). The results of the in vivo study indicate that PRLT can inhibit the observed increase of gastric juice volume and decrease of gastric juice pH caused by gastric injury. PRLT can decrease the serum levels of IL-6 (interleukin-6), IL-12 (interleukin-12), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) in mice with gastric injuries. Moreover, it can also increase the serum levels of SS (somatostatin) and VIP (vasoactive intestinal peptide) and reduce the serum levels of both SP (substance P) and ET-1 (endothelin-1). PRLT was also shown to increase SOD (superoxide dismutase) and GSH (glutathione) levels and decrease MDA (malondialdehyde) level. The detection of mRNA and protein in gastric tissues indicates that PRLT could also up-regulate the expression of Cu/Zn-SOD (copper/zinc superoxide dismutase), Mn-SOD (manganese superoxide dismutase), CAT (catalase), nNOS (neuronal nitric oxide synthase), and eNOS (endothelial nitric oxide synthase) and down-regulate the expression of both iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2). Thus, PRLT possess a good preventive effect on gastric injury, which is directly related to the contained active substance. PRLT show good anti-oxidative and preventive effect in gastric injury and offer promising application value.

Perrault syndrome (<em>PRLTS</em>) is a clinically and genetically heterogeneous disorder. Both male and female patients suffer from sensory neuronal hearing loss in early childhood, and female patients are characterized by premature ovarian failure and infertility after puberty. Clinical diagnosis may not be possible in early life, because key features of <em>PRLTS</em>, for example infertility and premature ovarian failure, do not appear before puberty. Limb spasticity, muscle weakness, and intellectual disability have also been observed in <em>PRLTS</em> patients. Mutations in five genes, HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of <em>PRLTS</em>. We discovered a consanguineous Saudi family with the <em>PRLTS</em>3 phenotype showing an autosomal recessive mode of inheritance. The patients had developed profound hearing loss, brain atrophy, and lower limb spasticity in early childhood. For molecular diagnosis, we complimented genome-wide homozygosity mapping with whole exome sequencing analyses and identified a novel homozygous mutation in exon 6 of CLPP at chromosome 19p13.3. To our knowledge, early onset with regression is a unique feature of these <em>PRLTS</em> patients that has not been reported so far. This study broadens the clinical spectrum of <em>PRLTS</em>3.

Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent individuals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3-Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.

In the present study, we used 22 microsatellite markers flanking to or within 13 known or candidate tumor suppressor genes (TSGs) to detect loss of heterozygosity (LOH) in these chromosomal regions among 41 cases of non-small cell lung cancer, including 28 squamous cell carcinoma (SCC) and 13 adenocarcinoma (ADC). The studied TSGs comprised FHIT, VHL, APC, PRLTS, p16, IFNA, PTEN, p57, ATM, p53, BRCA1, DPC4 and DCC. Our data demonstrated frequent allelic losses of FHIT, p53, IFNA, VHL and p16 in both SCC and ADC. PTEN and ATM showed the least frequency of LOH, while no deletion of BRCA1 was detected in all tumor samples. LOH analysis of PRLTS was extended to 26 cases of ADC, which demonstrated significantly higher frequency of LOH than SCC. Our data indicated a possible correlation between specific TSG(s) and either histological type of lung cancer, and more attention should be paid to the PRLTS gene, which might play an important role in the development of ADC.

Earlier, we established that a major drought tolerance QTL on linkage group 2 of pearl millet is also associated with reduced salt uptake and enhanced growth under salt stress. Present study was undertaken to re-assess the performance of drought tolerant (PRLT 2/89-33) and drought sensitive (H 77/833-2) parents along with two QTL-NILs (ICMR 01029 and ICMR 01040), under salinity stress specifically imposed during post-flowering growth stages when plants had developed their ion sinks in full. Time course changes in ionic accumulation and their compartmentalization in different plant parts was studied, specifically to monitor and capture changes conferred by the two alleles at this QTL, at small intervals. Amongst different plant parts, higher accumulation of toxic ion Na+ was recorded in roots. Further, the Na+ concentration in roots of the testcross hybrid of the drought-sensitive parent (H 77/833-2) reached its maximum at ECiw 15 dS m-1 within 24 h after salinity imposition, whereas it continued to increase with time in the testcross hybrids of the drought tolerant parent PRLT 2/89-33 as well as those of its QTL-NILs (ICMR 01029 and ICMR 01004) and reached at its maximum at 120 h stage. Comparison of differential distribution of toxic ions in individual leaves revealed that Na+ ions were not uniformly distributed in the leaves of the drought-tolerant parent and drought-tolerant QTL-NILs; but accumulated preferentially in the older leaves, whereas the hybrid of the drought-sensitive parent showed significantly higher Na+ concentration in all main stem leaves irrespective of their age. Dynamics of chlorophyll and proline concentration variation studied under salt stress at late flowering stages revealed a greater reduction, almost twice, in both leaf chlorophyll and proline concentrations in younger leaves in the hybrids of the sensitive parent as compared to the tolerant parent and QTL NILs. Imposition of salinity stress even at flowering stage affected the yield performance in pearl millet, wherein higher yield was recorded in drought tolerant parent and the two QTL-NILs compared to drought sensitive parent.

Metastatic castration-resistant prostate cancer (mCRPC) patients have been started to treat with prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT), especially with Lu-177 PSMA-617 in recent years. But, side effects of PRLT against salivary glands, limits the treatment safety. Current study aims to show the effect of external cooling with icepacks on Lu-177 PSMA-617 uptake in parotid glands (PGs). Methods: Nineteen patients (Mean age 72.9 years) who had pre-treatment Gallium-68 (Ga-68) PSMA-11 Positron emission tomography/Computed tomography (PET/CT) with mCRPC referred for the first time for Lu-177 PSMA-617 treatment were included. Maximum and mean standard uptake values (SUV_max and SUVmean) of right (R) and left (L) PGs were measured on Ga-68 PSMA PET/CT before treatment without ice-pack applications. Before the initiation of PRLT, frozen icepacks were fixated unilaterally (all right sided) on PGs' of patients and applied approximately 5 hours. 4th and 24th h of PRLT, whole body planar scintigraphy images and 4th hour head/neck region single photon emission computed tomography/ computed tomography (SPECT/CT) scans were acquired after injection of Lu-177 PSMA-617. Region of interest (ROI) for R and L PGs and volume of interest (VOI) of SPECT counts, volume of CT of 4th hour R and L PGs were calculated. Results: Before the PRLT, Ga-68 PSMA-11 PET/CT scan without icepack application, showed no statistical significance between R and L PGs' SUV_max or SUVmean variables (p>.05). In the 4th and 24th hour of PRLT, on the planar images externally cooled R PGs' ROI's did not demonstrated any statistical difference when compared with L PGs which were not externally cooled(p>.05). SPECT/CT images in the 4th hour of PRLT had no statistical difference between R and L PGs' VOI counts. In addition, volumes of R and L PGs did not show any statistical difference between the glands (p>.05). Conclusion: External cooling of PGs in order to reduce Lu-177 PSMA-617 uptake with icepacks is not working at all.

Since loss of heterozygosity on 8p22-p21.3 has been found frequently in prostate cancer, the status of a candidate tumor suppressor gene named PRLTS gene, recently cloned from the same region in some human malignancies, was examined in the present study. DNAs were isolated from 69 Japanese prostate cancer patients (37 localized and 32 cancer-death cases). Loss of heterozygosity at this gene locus was observed in 15 of 36 (42%) localized prostate cancer patients and 22 of 32 (69%) cancer-death patients. One cancer-death patient had a missense mutation, ACG->>ATG (Thr->>Met) at codon 64 in metastatic tumor tissues of pelvic lymph node and liver, and these tissues showed loss of the homologous allele, indicating that "two-hit" mutation of the PRLTS gene had occurred in this case. The others did not show any mutation, regardless of the presence or absence of loss of heterozygosity. Although loss of heterozygosity at the PRLTS gene locus is a relatively common abnormality, mutation of this gene is rare in prostate cancer.

Perrault syndrome (PRLTS) is a heterogeneous group of clinical and genetic disorders characterized by sensory neuronal hearing loss in both sexes and premature ovarian failure or infertility in females. Neurological and hearing loss symptoms appear early in life, but female infertility cannot be detected before puberty. Spastic limbs, muscle weakness, delayed puberty and irregular menstrual cycles have also been observed in PRLTS patients. Mutations in five genes, i.e. HSD17B4, HARS2, CLPP, LARS2, and C10orf2, have been reported in five subtypes of PRLTS. Here, we report a milder phenotype of PRLTS in a Turkish family in which two affected patients had no neurological findings. However, both were characterized by sensory neuronal hearing loss and the female sibling had secondary amenorrhea and gonadal dysgenesis. Genome-wide homozygosity mapping using 300K single-nucleotide polymorphism microarray analysis together with iScan platform (Illumina, USA) followed by candidate gene Sanger sequencing with ABI 3500 Genetic Analyzer (Life Technologies, USA) were used for molecular diagnosis. We found a novel missense alteration c.624C>G; p.Ile208Met in exon 5 of the CLPP at chromosome 19p13.3. This study expands the mutation spectrum of CLPP pathogenicity in PRLTS type 3 phenotype.

Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D.

To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]).

Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.

The primary end point was OS.

Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.

There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.

Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.