Large-scale sequencing of genomic regions and in silico gene trapping together represent a highly efficient and powerful approach for identifying novel genes. We performed megabase-level sequence analyses of two genomic regions on human chromosome 8p (8p11.2 and 8p22->>p21.3), after covering those segments with sequence-ready contigs composed of 74 cosmids, 14 BACs, and three PAC clones. We determined continuous nucleotide sequences of 1,856,753 bases on 8p11.2 and 1,210,381 bases on 8p22->>p21.3 by combining the shotgun and primer-walking methods. In silico gene trapping identified four novel genes in the 8p11.2 region and, in the 8p22->>p21.3 region, six known genes (PRLTS, PCM1, MTAMR7, HCAT2, HFREP-1 and PHP) and three novel genes. The distribution of Alu and LINE1 repetitive elements and the densities of predicted exons were different in each region, and Alu-rich portions contained more exonic sequences than LINE1-rich areas.

Background: Behavioral flexibility -the ability to dynamically readjust our behavior in response to reward contingency changes- is often investigated using probabilistic reversal learning tasks (PRLT). Poor PRLT performance has been proposed as a proxy for compulsivity, and theorized to be related to perseverative gambling. Previous attempts to measure inflexibility with the PRLT in patients with gambling disorder have, however, used a variety of indices that may conflate inflexibility with more general aspects of performance in the task.

Methods: Trial-by-trial PRLT acquisition and reacquisition curves in 84 treatment-seeking patients with gambling disorder and 64 controls (non-gamblers and non-problem recreational gamblers) were analyzed to distinguish between (a) variability in acquisition learning, and (b) reacquisition learning in reversed contingency phases. Complementarily, stay/switch responses throughout the task were analyzed to identify (c) premature switching, and (d) sensitivity to accumulated negative feedback.

Results and interpretation: Even after controlling for differences in acquisition learning, patients were slower to readjust their behavior in reversed contingency phases, and were more prone to maintain their decisions despite accumulated negative feedback. Inflexibility in patients with gambling disorder is thus a robust phenomenon that could predate gambling escalation, or result from massive exposure to gambling activities.

Keywords: Compulsivity; Decision-making under ambiguity; Gambling disorder; Instrumental learning; Reversal learning; Reward-based learning.

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n = 84) were treated with vehicle, 0.03, or 0.3 mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3 mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed.

Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral (liver or lung) metastases have a poor prognosis and worse outcomes than those with bone disease with or without lymph nodes involvement. The high prostate-specific membrane antigen expression in prostate cancer metastases makes it a promising approach for targeted radionuclide therapy of prostate cancer. Lutetium-177 (Lu)-labeled prostate-specific membrane antigen radioligand therapy (Lu-PRLT) has demonstrated encouraging efficacy in mCRPC. We report here an mCRPC patient with lung, lymph nodes, and extensive bone metastases, who underwent Lu-PRLT and had excellent response to the treatment and complete regression of lung metastases after Lu-PRLT.

Objectives: To develop and examine a scoring system in metastatic castration-resistant prostate carcinoma (mCRPC) that integrates findings of both 68Ga-prostate-specific membrane antigen (PSMA) and flurodeoxyglucose (FDG) PET-CT imaging in a single combined parameter and referred to as the 'Pro-PET' score.

Methods: A six-tier integrated dual tracer PET-CT (68Ga-PSMA and FDG) Image Scoring System ('Pro-PET' score) was conceptualized, based on the findings of both 68Ga-PSMA-11 and FDG PET-CT in patients of mCRPC. This proposed integrated scoring was examined in a retrospective analytical study assessing mCRPC patients (n = 47) referred for 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) and had both FDG and 68Ga-PSMA PET-CT undertaken within 15 days of each other without any interim treatment intervention. The 'Pro-PET' score grades and subgrades were assigned and compared with clinical data, such as histopathology, Gleason score, serum prostate-specific antigen (PSA), treatment response (symptomatic, biochemical, metabolic and anatomical) and survival [overall survival (OS) and progression-free survival (PFS)].

Results: The Pro-PET score significantly correlated with symptomatic (P = 0.05), biochemical (P = 0.05), metabolic (P = 0.001) and anatomical (P = 0.012) responses, PFS (P = 0.03) and OS (P = 0.027). On multivariate analysis, histopathology, Gleason score and PSA as individual parameters were not significantly associated with OS and PFS, whereas the Pro-PET score was found to have a significant association (P = 0.001 for PFS and 0.011 for OS).

Conclusion: The 'Pro-PET' scoring system integrating dual tracer PET-CT imaging findings in a single parameter appeared as a potentially promising prognostic marker that has the potential to enhance the objectivity and scientific basis of prostate carcinoma theranostics and prognostication.

Bulimia nervosa (BN) is characterized by recurrent engagement in eating disorder behaviors despite negative consequences, potentially reflecting aberrant stimulus-response or reward-learning processes. Indeed, frontostriatal circuitry involved in reward learning is altered in persons with BN and preliminary research suggests reward learning is impaired in persons with BN. Additional research on reward learning in BN and its association with eating disorder symptom expression is warranted to further the field's understanding of potential pathophysiological mechanisms of BN. To this end, the probabilistic reward learning task (PRLT) was administered to unmedicated women with BN (n = 15) and demographically matched psychiatrically healthy women (n = 18). Contrary to our hypotheses, results demonstrated that women with BN showed greater reward learning during the PRLT relative to healthy comparison women when covarying for symptoms of depression, social anxiety, and mania. Exploratory analyses showed that binge-eating frequency was inversely associated with reward learning in women with BN; however, results should be interpreted with caution due to the small sample size. Together, results suggest that women with BN do not have deficits in implicit reward learning. Given the preliminary nature of this investigation, larger-scale studies are needed to further examine reward learning in current BN and could compare reward learning using general (e.g., monetary) and disorder-specific (e.g., food) reinforcers. Further work is needed to confirm the inverse association between reward learning and binge eating.

Keywords: Bulimia nervosa; Probabilistic reward learning task; Reward learning.

Traits influencing plant water use eventually define the fitness of genotypes for specific rainfall environments. We assessed the response of several water use traits to vapour pressure deficit (VPD) in pearl millet (Pennisetum glaucum (L.) R.Br.) genotypes known to differ in drought adaptation mechanisms: PRLT 2/89-33 (terminal drought-adapted parent), H 77/833-2 (terminal drought-sensitive parent) and four near-isogenic lines introgressed with a terminal drought tolerance quantitative trait locus (QTL) from PRLT 2/89-33 (ICMR01029, ICMR01031, ICMR02042, and ICMR02044). Plant water use traits at various levels of plant organisation were evaluated in seven experiments in plants exposed either transiently or over the long term to different VPD regimes: biomass components, transpiration (water usage per time unit) and transpiration rate (TR) upon transient VPD increase (gH2Ocm-2h-1)), transpiration efficiency (g dry biomass per kg H2O transpired), leaf expansion rate (cm per thermal time unit) and root anatomy (endodermis dimensions)). High VPD decreased biomass accumulation by reducing tillering, the leaf expansion rate and the duration of leaf expansion; decreased root endodermis cell size; and increased TR and the rate of TR increase upon gradual short-term VPD increases. Such changes may allow plants to increase their water transport capacity in a high VPD environment and are genotype-specific. Some variation in water use components was associated with terminal drought adaptation QTL. Knowledge of water use traits' plasticity in growth environments that varied in evaporative demand, and on their genetic determinacy, is necessary to develop trait-based breeding approaches to complex constraints.

Genotypic differences in transpiration rate responses to high vapour pressure deficit (VPD) was earlier reported. Here we tested the hypothesis that this limitation could relate to different degrees of dependence on the apoplastic (spaces between cells), and symplastic water transport pathways (through cells via aquaporin-facilitated transport), which are known to have different hydraulic conductivities. The low transpiration rate (Tr) genotype PRLT 2/89/33 either restricted its transpiration under high VPD, or was more sensitive to VPD than H77/833-2, when grown hydroponically or in soil. The slope of the transpiration response to an ascending series of VPD was lower in whole plants than in de-rooted shoots. In addition, the transpiration response of detached leaves to moderately high VPD (2.67kPa), normalised against leaves exposed to constant VPD (1.27kPa), was similar in low and high Tr genotypes. This suggested that roots hydraulics were a substantial limitation to water flow in pearl millet, especially under high VPD. The dependence on the apoplastic and symplastic water transport pathways was investigated by assessing the transpiration response of plants treated with inhibitors specific to the AQP-mediated symplastic pathway (AgNO3 and H2O2) and to the apoplastic pathway (precipitates of Cu(Fe(CN)6) or Cu(CuFe(CN)6)). When CuSO4 alone was used, Cu ions caused an inhibition of transpiration in both genotypes and more so in H77/833-2. The transpiration of high Tr H77/833-2 was decreased more by AQP inhibitors under low VPD (1.8kPa) than in PRLT 2/89/33, whereas under high VPD (4.2kPa), the transpiration of PRLT 2/89/33 was decreased more by AQP inhibitors than in H77/833-2. The transpiration rate of detached leaves from H77/833-2 when treated with AgNO3 decreased more than in PRLT 2/89/33. Although the root hydraulic conductivity of both genotypes was similar, it decreased more upon the application of a symplastic inhibitor in H77/833-2. The transpiration of low Tr PRLT 2/89/33 was decreased more by apoplastic inhibitors under both low and high VPD. Then the hydraulic conductivity decreased more upon the application of an apoplastic inhibitor in PRLT 2/89/33. In conclusion, both pathways contributed to water transport, and their contribution varied with environmental conditions and genotypes. Roots were a main source of hydraulic limitation in these genotypes of pearl millet, although a leaf limitation was not excluded. The similarity between genotypes in root hydraulic conductivity under normal conditions also suggests changes in this conductivity upon changes in the evaporative demand. The low Tr genotype depended more on the apoplastic pathway for water transport, whereas the high Tr genotype depended on both pathway, may be by 'tuning-up' the symplastic pathway under high transpiration demand, very likely via the involvement of aquaporins.

Development of radiochemistry and hybrid technology resulted in a new era in the management of prostate cancer. Choline PET provides more sensitive and accurate diagnosis, and it can support the personalized, metastases-directed therapies. PSMA radioligands are used as theranostics worldwide but are not available in Hungary. 68Ga- or 18F-labelled molecules are excellent diagnostic agents which can detect the primary process and its metastases more sensitively than choline, especially at lower PSA levels. 177Lu-labelled PSMA ligand as a therapeutic pair of the diagnostic molecules can provide an effective therapeutic option in metastatic castration resistant prostate cancer. In this publication we review PSMA radioligand therapy (PRLT) in management of prostate cancer based on the recently published European guideline.

The HIV transgenic (HIVtg) rat is a commonly used animal model of chronic HIV infection that exhibits a wide range of cognitive deficits. To date, relatively little work has been conducted on these rats' capacity for reversal learning, an assay of executive function and cognitive flexibility used in humans. The present study sought to determine the impact of HIV genotype on probabilistic reversal learning, effortful motivation, and spontaneous locomotion/exploration in rats. Male (n = 8) and female (n = 8) HIVtg rats and wildtype (WT) controls were utilized. Cognitive flexibility was assessed via the Probabilistic Reversal Learning Task (PRLT), which reinforced responses to two stimuli on differential probabilistic schedules that periodically reversed. Effortful motivation and locomotor/exploratory behavior were assessed via the Progressive Ratio Breakpoint Task (PRBT) and the Behavioral Pattern Monitor (BPM), respectively. Regardless of sex, HIVtg rats required fewer trials to ascertain initial PRLT reward schedules than WT rats, and completed the same number of reversals. Secondary behaviors suggested that HIVtg PRLT performance was facilitated by a speed-accuracy tradeoff strategy. No main or interactive effects of genotype were observed in the PRBT or BPM. Relative to WT controls, HIVtg rats exhibited superior probabilistic reinforcement learning. Reversal learning was unaffected by HIV genotype, as was effortful motivation and exploratory behavior. These findings contrast with previous characterizations of the HIVtg rat, thus indicating a nuanced cognitive profile that is dependent upon such task specifications as within- versus between-session assessment and probabilistic versus deterministic reward schedules.

Keywords: Effortful motivation; HAND; HIV transgenic rat; Probabilistic learning; Reversal learning.

Background: Decisions made by individuals with disordered gambling are markedly inflexible. However, whether anomalies in learning from feedback are gambling-specific, or extend beyond gambling contexts, remains an open question. More generally, addictive disorders-including gambling disorder-have been proposed to be facilitated by individual differences in feedback-driven decision-making inflexibility, which has been studied in the lab with the Probabilistic Reversal Learning Task (PRLT). In this task, participants are first asked to learn which of two choice options is more advantageous, on the basis of trial-by-trial feedback, but, once preferences are established, reward contingencies are reversed, so that the advantageous option becomes disadvantageous and vice versa. Inflexibility is revealed by a less effective reacquisition of preferences after reversal, which can be distinguished from more generalized learning deficits.

Methods: In the present study, we compared PRLT performance across two groups of 25 treatment-seeking patients diagnosed with an addictive disorder and who reported gambling problems, and 25 matched controls [18 Males/7 Females in both groups, M_age(SD_age) = 25.24 (8.42) and 24.96 (7.90), for patients and controls, respectively]. Beyond testing for differences in the shape of PRLT learning curves across groups, the specific effect of problematic gambling symptoms' severity was also assessed independently of group assignment. In order to surpass previous methodological problems, full acquisition and reacquisition curves were fitted using generalized mixed-effect models.

Results: Results showed that (1) controls did not significantly differ from patients in global PRLT performance nor showed specific signs of decision-making inflexibility; and (2) regardless of whether group affiliation was controlled for or not, gambling severity was specifically associated with more inefficient learning in phases with reversed contingencies.

Conclusion: Decision-making inflexibility, as revealed by difficulty to reacquire decisional preferences based on feedback after contingency reversals, seems to be associated with gambling problems, but not necessarily with a substance-use disorder diagnosis. This result aligns with gambling disorder models in which domain-general compulsivity is linked to vulnerability to develop gambling-specific problems with exposure to gambling opportunities.

Keywords: Addictive disorders; Compulsivity; Gambling disorder; Gambling severity; Learning inflexibility; Probabilistic reversal learning task.

Prostate-specific membrane antigen (PSMA) is an attractive target for the diagnosis and therapy of prostate cancer as it is specifically overexpressed in prostate cancer cells. Improving the circulation of radioligands in the blood is considered as an effective strategy that can improve tumor burden, which benefits detection of small lesions and improves the effect of PSMA radioligand therapy (PRLT). In this study, we introduced maleimidopropionic acid (MPA) to a PSMA-targeted tracer and developed Al¹⁸F-PSMA-CM, which targets human serum albumin (HSA) binding and PSMA. Al¹⁸F-PSMA-CM is evaluated in vitro and in vivo for stability, PSMA specificity, and biodistribution in 22Rv1 tumor-bearing mice. Al¹⁸F-PSMA-CM was prepared with a radiochemical purity of >99% and specific activity of 11.22-18.70 MBq/nmol. Al¹⁸F-PSMA-CM was stable in vitro and in vivo and prolonged circulation in blood with a binding ratio of 47 ± 3.2% and Kd value of 3.08 ± 0.45 nM to HSA. The uptake of Al¹⁸F-PSMA-CM in PSMA(+) 22Rv1 cells was increased in 2 h, and the uptake was blocked by a PSMA inhibitor, ZJ-43. The Kd value of Al¹⁸F-PSMA-CM to PSMA was 8.46 ± 0.24 nM. Al¹⁸F-PSMA-CM was accumulated in kidneys and 22Rv1 tumors [74.76 ± 15.42 and 6.16 ± 0.74 ID%/g at 2 h post injection (p.i.)], which were decreased by -80.0 and -84.3% when co-injected with ZJ-43. Al¹⁸F-PSMA-CM showed high PSMA specificity and accumulated in 22Rv1 tumors with increasing uptake in 4 h. MPA moiety showed the ability to prolong the half-life of tracers, and the MPA-conjugated tracer showed the potential to improve tumor uptake. MPA may be a choice to develop radiopharmaceuticals for PRLT of prostate cancer.

Keywords: Al18F; Micro-PET; PRLT; PSMA; albumin; maleimidopropionic acid.

Perrault syndrome (<em>PRLTS</em>) is a rare autosomal recessive disorder characterised by ovarian failure in females and sensorineural hearing loss (SNHL) in both genders. In the present paper we describe a child affected by <em>PRLTS</em>3, due to CLPP homozygous mutations, presenting auditory neuropathy spectrum disorder (ANSD) with bilateral progressive SNHL. This is the first case reported in the literature of an ANSD in <em>PRLTS</em>3. CLPP is a nuclear encoded mitochondrial protease directed at the mitochondrial matrix. It is encoded on chromosome 19. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining the normal metabolic function of the cell. In <em>PRLTS</em>3, the peptidase activity of CLPP is suppressed. Neurological impairments involved in <em>PRLTS</em>3 suggest that the pathogenic mutations in CLPP might trigger a mitochondrial dysfunction. A comprehensive description of the clinical and audiological presentation, as well as the issues related to cochlear implant (CI) procedure and the results, are addressed and discussed. A brief review of the literature on this topic is also provided.

Keywords: Perrault syndrome; auditory neuropathy spectrum disorder; cochlear implant.

Extreme climatic conditions like drought are a major threat to global food production. Terminal drought stress causes severe yield losses in pearl millet. Development of climate-resilient varieties/hybrids can minimize the yield losses to the farmers caused due to climatic extremes. In the present study, marker-assisted selection (MAS) was employed with an aim to develop improved version of HHB 226 by introgression of QTLs for terminal drought stress tolerance into the male parent of the hybrid (HBL 11). HBL 11 (recurrent parent) was crossed with PRLT 2 (donor) to develop F₁ and backcrossed four times to raise BC₄F₁ and further selfed twice to raise BC₄F₃. Four polymorphic SSR markers were used to track the QTL introgressed lines in each subsequent generation until BC₄F₂. The recurrent parent genome recovery was assessed using 25 polymorphic SSRs. Morpho-physiological analysis of BC₄F₃ generation at field-level under terminal drought stress conditions showed that the QTL introgressed lines showed higher, grain yield, 1000-seed weight, relative water content (%), and lower electrolyte leakage (%) than the recurrent parent. Line number 63 performed best with all the four foreground markers, 97.20% recurrent parent genome recovery, 7.27 g 1000-seed weight, 73.27% relative water content, 65.06% electrolyte leakage, 0.58 (fv/fm) chlorophyll fluorescence, and 53.25 g grain yield per plant. Finally, the Improved version of HHB 226 was developed by using the Improved HBL 11 developed through MAS. Besides this, HBL 11 is the male parent of other commercial hybrids like HHB 223 and HHB 197 as well making Improved HBL 11 an asset to improve these pearl millet hybrids.

Objective: The aim of present study was to determine and compare the overall response rates, progression-free survival (PFS), overall survival (OS), and clinical toxicity of the combination of 177Lu-PSMA-617 radioligand therapy (PRLT) and abiraterone acetate (AA) versus 177Lu-PSMA-617 PRLT as monotherapy in metastatic castration-resistant prostate cancer (mCRPC) patients.

Materials and methods: The mCRPC patients who received at least one cycle of ¹⁷⁷ Lu-PSMA-617 PRLT with or without AA therapy, were included and analyzed in the present study. The patients were divided into two major groups. Group 1 received only ¹⁷⁷ Lu-PSMA PRLT and Group 2 received combined ¹⁷⁷ Lu-PSMA PRLT + AA therapy. Therapeutic dose of ¹⁷⁷ Lu-PSMA-617 PRLT was 4.4-5.55 GBq per patient per cycle administered at intervals of 10-12 weeks in both groups. The Group 2 patients additionally received a dose of 1000 mg of AA once daily and 5 mg of prednisone twice daily. Treatment response in two groups was evaluated under four broad categories (a) symptomatic, (b) biochemical (serum prostate-specific antigen level), (c) objective molecular imaging (⁶⁸ Ga-PSMA-11 and ¹⁸ F-FDG PET/CT), and (d) objective anatomical imaging (computed tomography). For assessing treatment response, patients in two groups were categorized into responders (complete response [CR], partial response [PR], and stable disease [SD]) and nonresponders (progressive disease [PD]). The Kaplan-Meier product-limit method was used to calculate PFS and OS following first ¹⁷⁷ Lu-PSMA PRLT in the two groups. Univariate analysis was used to compare the patients' characteristics in two groups using a χ² or Fisher exact test. The Kaplan-Meier curves of PFS and OS between two groups were compared by using the log-rank test (p < 0.05 significant).

Results: A total of 58 mCRPC patients (Group 1, 38 patients and Group 2, 20 patients) were included in this study analysis. The clinical and demographic characteristics of these patients (age, Gleason score, FDG avid disease, metastatic disease burden, and average number of ¹⁷⁷ Lu-PSMA PRLT cycles) in two groups were compared and found to be similar (p > 0.05). Post-treatment, symptomatic, biochemical, molecular, and anatomic imaging responders were found in 22 patients (58%) and 17 patients (85%), 22 patients (58%) and 16 patients (80%), 19 patients (54%) and 14 patients (78%), and 19 patients (54%) and 14 patients (78%) in Group 1 and Group 2, respectively. The median PFS of 7 months and median OS of 8 months were documented in Group 1, whereas median PFS was not reached and median OS of 16 months registered in Group 2. Transient hematological toxicity of Grades 1 and 2 was found in total seven patients (five patients in Group 1 and two patients in Group 2). On comparison of the treatment outcome between two groups, significant p value was found for symptomatic responders (58% in Group 1 vs. 85% in Group 2), median PFS (7 months in Group 1 vs. not reached in Group 2), and median OS (8 months in Group 1 vs. 16 months in Group 2), with better outcome in Group 2 patients for these variables.

Conclusion: In the present study, the combination of ¹⁷⁷ Lu-PSMA-617 PRLT and AA therapy showed significant improvement in mCRPC patients' symptomatic response, PFS, and OS as compared to ¹⁷⁷ Lu-PSMA-617 PRLT monotherapy.

Keywords: 177Lu-PSMA-617; 68Ga-PSMA PET-CT; FDG PET-CT; PERCIST; PSA doubling time; RECIST; abiraterone; metastatic castrate-resistant prostate carcinoma; peptide receptor radioligand therapy; progression-free survival and overall survival.

Background: Determining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT).

Method: In this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51-88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6-12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS.

Results: A total of 112 cycles of PRLT with a median of 3 cycles (range: 1-6) and median administered activity per cycle of 6.29 GBq (range: 4.45-7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/μL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥ 115 ng/mL, cumulative dose of ¹⁷⁷Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS. In multivariable Cox regression analysis, higher baseline platelet count, lower baseline hemoglobin, superscan pattern, and lower cumulative dose of ¹⁷⁷Lu-PSMA remained significant predictors of poor OS.

Conclusion: PRLT with ¹⁷⁷Lu-PSMA is well-tolerated and effective in metastatic prostate cancer patients who have no other treatment options available. The novel prognostic markers found in this study (high platelet count, superscan pattern) were associated with poor overall survival.

Keywords: (177)Lu-PSMA; Cáncer de próstata; PRLT; PSA; Prostate cancer.

Task-based measures that capture neurocognitive processes can help bridge the gap between brain and behavior. To transfer tasks to clinical application, reliability is a crucial benchmark because it imposes an upper bound to potential correlations with other variables (e.g., symptom or brain data). However, the reliability of many task readouts is low. In this study, we scrutinized the retest reliability of a probabilistic reversal learning task (PRLT) that is frequently used to characterize cognitive flexibility in psychiatric populations. We analyzed data from N = 40 healthy subjects, who completed the PRLT twice. We focused on how individual metrics are derived, i.e., whether data were partially pooled across participants and whether priors were used to inform estimates. We compared the reliability of the resulting indices across sessions, as well as the internal consistency of a selection of indices. We found good to excellent reliability for behavioral indices as derived from mixed-effects models that included data from both sessions. The internal consistency was good to excellent. For indices derived from computational modeling, we found excellent reliability when using hierarchical estimation with empirical priors and including data from both sessions. Our results indicate that the PRLT is well equipped to measure individual differences in cognitive flexibility in reinforcement learning. However, this depends heavily on hierarchical modeling of the longitudinal data (whether sessions are modeled separately or jointly), on estimation methods, and on the combination of parameters included in computational models. We discuss implications for the applicability of PRLT indices in psychiatric research and as diagnostic tools.

Keywords: Computational modeling; Hierarchical modeling; Probabilistic reversal learning; Reinforcement learning; Reliability.

Prostate-specific membrane antigen (PSMA) is highly expressed on the membrane of most prostate cancer cells and to a lesser extent in normal tissues. Many vectors targeting this protein have been created over the past decade and numerous clinical studies have positively demonstrated the tolerance and efficacy of radiolabeled prostate-specific membrane antigen ligands for PSMA radioligand therapy (PRLT). Preliminary results are encouraging that PRLT will become an important addition to the current therapeutic options in a number of settings. Improvement in radiopharmaceutical targeting and combination with other oncological agents are under investigation to further improve its therapeutic efficacy. These encouraging results have led to the development of other therapies using PSMA as a target, such as PSMA-targeted chimeric antigen receptor T-cells, PSMA-targeted antibody drug conjugates, and PSMA-targeted bi-specific T-cell-directed therapy. This narrative review details the current state and advancements in prostate-specific membrane antigen targeting in prostate cancer treatment.

Keywords: PSMA; immunotherapy; prostate cancer; radionuclide therapy.

Background: Perrault syndrome (PRLTS) is a rare autosomal recessive disorder characterized by sensorineural hearing loss in both sexes and ovarian dysfunction in females. In some cases, patients present with a diversity of neurological signs. Six genes are known to cause Perrault syndrome.

Case report: We report an 11-year-old Chinese girl with delayed gonadal development, sensorineural hearing loss, and neurologic manifestations. Genetic etiology was identified by whole-exome sequencing and confirmed via Sanger sequencing. Compound heterozygous variants with one novel variant c.1752C>A (p.D584E) and one known pathogenic variant c.1172G>A (p.R391H) in TWNK were discovered in the child and inherited from her parents, respectively.

<strong class="sub-title"> Conclusion: </strong> The compound heterozygous variants c.1172G>A (p.R391H) and c.1752C>A (p.D584E) of the <i>TWNK</i> gene probably underlie <em>PRLTS</em> type 5 (<em>PRLTS</em>5). This study expands the mutation spectrum of <i>TWNK</i> pathogenicity in the <em>PRLTS</em>5 phenotype.

Keywords: Chinese; Perrault syndrome; TWNK gene; whole-exome sequencing.