Miracle-dz/UniFAR-FTUs huggingface dataset:
Intensive chemotherapy and consolidation with high dose therapy and autologous stem cell transplant in patients with mantle cell lymphoma

Abstract Mantle cell lymphoma (MCL) remains incurable with conventional chemotherapy without consensus on the optimal initial treatment. We examined our single center experience with frontline therapy for patients with MCL in consecutive cases diagnosed 1995-2011. Among 81 patients, median age was 59 (28% were ≥ 65 years of age), 95% had stage III/IV disease and 54% had a low risk MCL International Prognostic Index score. Thirty-five percent (n = 28) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 65% received R-HCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate/cytarabine; n = 53). Forty-one patients were consolidated with autologous stem cell transplant (ASCT). There were no significant differences in 2-year survival for R-CHOP versus R-HCVAD (p = 0.10) or for ASCT versus observation (p = 0.06). After controlling for clinical factors, R-HCVAD followed by ASCT was associated with superior progression-free survival (hazard ratio 0.26, 95% confidence interval 0.09–0.75).
Serotonergic Integration of Circadian Clock and Ultradian Sleep–Wake Cycles

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus generates a 24 h rhythm of sleep and arousal. While neuronal spiking activity in the SCN provides a functional circadian oscillator that propagates throughout the brain, the ultradian sleep–wake state is regulated by the basal forebrain/preoptic area (BF/POA). How this SCN circadian oscillation is integrated into the shorter sleep–wake cycles remains unclear. We examined the temporal patterns of neuronal activity in these key brain regions in freely behaving rats. Neuronal activity in various brain regions presented diurnal rhythmicity and/or sleep–wake state dependence. We identified a diurnal rhythm in the BF/POA that was selectively degraded when diurnal arousal patterns were disrupted by acute brain serotonin depletion despite robust circadian spiking activity in the SCN. Local blockade of serotonergic transmission in the BF/POA was sufficient to disrupt the diurnal sleep–wake rhythm of mice. These results suggest that the serotonergic system enables the BF/POA to couple the SCN circadian signal to ultradian sleep–wake cycles, thereby providing a potential link between circadian rhythms and psychiatric disorders.
Assessment practices of Irish occupational therapists: a study

Assessment is a key component of the occupational therapy intervention process. Standardized assessments provide objectivity to this process. It is important that, in addition, these assessments reflect the client-centred philosophy of the profession. This article addresses key issues regarding the use of standardized assessments, and reports on the results of a study investigating the assessment practices of a group of Irish occupational therapists. The purpose of this article is to identify the attributes of standardized assessments and to question their place within the practice of occupational therapy. Occupational therapy philosophy stresses the importance of a client-centred approach to intervention, where the client's problems, needs and priorities are determined by the client or by the therapist in collaboration with the client or care giver. Many of the current standardized tests lack this client-centred approach. This article looks at current assessment practices among a group of Irish occupatio.
Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer

Previously, we showed that high-energy metabolites (lactate and ketones) “fuel” tumor growth and experimental metastasis in an in vivo xenograft model, most likely by driving oxidative mitochondrial metabolism in breast cancer cells. To mechanistically understand how these metabolites affect tumor cell behavior, here we used genome-wide transcriptional profiling. Briefly, human breast cancer cells (MCF7) were cultured with lactate or ketones, and then subjected to transcriptional analysis (exon-array). Interestingly, our results show that treatment with these high-energy metabolites increases the transcriptional expression of gene profiles normally associated with “stemness,” including genes upregulated in embryonic stem (ES) cells. Similarly, we observe that lactate and ketones promote the growth of bonafide ES cells, providing functional validation. The lactate- and ketone-induced “gene signatures” were able to predict poor clinical outcome (including recurrence and metastasis) in a cohort of human breast cancer patients. Taken together, our results are consistent with the idea that lactate and ketone utilization in cancer cells promotes the “cancer stem cell” phenotype, resulting in significant decreases in patient survival. One possible mechanism by which these high-energy metabolites might induce stemness is by increasing the pool of Acetyl-CoA, leading to increased histone acetylation, and elevated gene expression. Thus, our results mechanistically imply that clinical outcome in breast cancer could simply be determined by epigenetics and energy metabolism, rather than by the accumulation of specific “classical” gene mutations. We also suggest that high-risk cancer patients (identified by the lactate/ketone gene signatures) could be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the anti-oxidant and “mitochondrial poison” metformin. Finally, we propose that this new approach to personalized cancer medicine be termed “Metabolo-Genomics,” which incorporates features of both 1) cell metabolism and 2) gene transcriptional profiling. Importantly, this powerful new approach directly links cancer cell metabolism with clinical outcome, and new therapeutic strategies for inhibiting the TCA cycle and mitochondrial oxidative phosphorylation in cancer cells.
Ribosomal stress induces L11- and p53-dependent apoptosis in mouse pluripotent stem cells

Ribosome biogenesis is the most demanding energetic process in proliferating cells and it is emerging as a critical sensor of cellular homeostasis. Upon disturbance of ribosome biogenesis, specific free ribosomal proteins, most notably L11, bind and inhibit Mdm2, resulting in activation of the tumor suppressor p53. This pathway has been characterized in somatic and cancer cells, but its function in embryonic pluripotent cells has remained unexplored. Here, we show that treatment with low doses of Actinomycin D or depletion of ribosomal protein L37, two well-established inducers of ribosomal stress, activate p53 in an L11-dependent manner in mouse embryonic stem cells (ESCs) and in induced pluripotent stem cells (iPSCs). Activation of p53 results in transcriptional induction of p53 targets, including p21, Mdm2, Pidd, Puma, Noxa and Bax. Finally, ribosomal stress elicits L11- and p53-dependent apoptosis in ESCs/iPSCs. These results extend to pluripotent cells the functionality of the ribosomal stress pathway and we speculate that this could be a relevant cellular checkpoint during early embryogenesis.
Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid β-Protein Oligomers

Microglial dysfunction is increasingly recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Environmental enrichment (EE) is well documented to enhance neuronal form and function, but almost nothing is known about whether and how it alters the brain's innate immune system. Here we found that prolonged exposure of naive wild-type mice to EE significantly altered microglial density and branching complexity in the dentate gyrus of hippocampus. In wild-type mice injected intraventricularly with soluble Aβ oligomers (oAβ) from hAPP-expressing cultured cells, EE prevented several morphological features of microglial inflammation and consistently prevented oAβ-mediated mRNA changes in multiple inflammatory genes both in vivo and in primary microglia cultured from the mice. Microdialysis in behaving mice confirmed that EE normalized increases in the extracellular levels of the key cytokines (CCL3, CCL4, TNFα) identified by the mRNA analysis. Moreover, EE prevented the changes in microglial gene expression caused by ventricular injection of oAβ extracted directly from AD cerebral cortex. We conclude that EE potently alters the form and function of microglia in a way that prevents their inflammatory response to human oAβ, suggesting that prolonged environmental enrichment could protect against AD by modulating the brain's innate immune system. SIGNIFICANCE STATEMENT Environmental enrichment (EE) is a potential therapy to delay Alzheimer's disease (AD). Microglial inflammation is associated with the progression of AD, but the influence of EE on microglial inflammation is unclear. Here we systematically applied in vivo methods to show that EE alters microglia in the dentate gyrus under physiological conditions and robustly prevents microglial inflammation induced by human Aβ oligomers, as shown by neutralized microglial inflammatory morphology, mRNA changes, and brain interstitial fluid cytokine levels. Our findings suggest that EE alters the innate immune system and could serve as a therapeutic approach to AD and provide new targets for drug discovery. Further, we propose that the therapeutic benefits of EE could extend to other neurodegenerative diseases involving microglial inflammation.
Evaluación Ultrasonográfica del Tejido Blando Facial en Adultos Chilenos

Existen variadas tecnicas para realizar la identificacion medicolegal en restos cadavericos u osamentas. Una de ellas es la identificacion por escultura forense. Para esto, se necesitan ciertas referencias en la relacion entre tejido oseo y tejido blando. El objetivo de esta investigacion fue determinar los grosores tisulares faciales mediante ultrasonografia y correlacionarlos con edad y sexo. Se selecciono una muestra de 48 personas, entre 21 y 50 anos de edad de ambos sexos, que consultaron al Servicio de Imagenologia de la Clinica Multimedica de Talca, Chile, distribuidas en dos grupos: A: 12 hombres y 12 mujeres entre 21 y 35 anos de edad, B: 12 hombres y 12 mujeres entre 36 y 50 anos de edad. Para este estudio se utilizo un ecografo General Electric®, modelo Voluson 730 expert, con el cual se midieron los grosores tistulares en 15 puntos medianos y paramedianos de la cabeza. Los resultados de la medicion de los grosores titulares mostraron diferencias significativas entre grupos etareos y sexos. No se observaron diferencias significativas, entre las personas del mismo sexo de un mismo grupo etareo
Contraceptive practices and awareness of emergency contraception among Muslim women of urban slum of Raichur, Karnataka -

Background: According to NFHS-2005, prevalence of female sterilization is lowest among Muslims (21 percent). Many women prefer not to use contraception and continue childbearing until they have at least one son. Proper use of family planning methods is the key to preventing unplanned pregnancies. This study aimed to assess the contraceptive practices and awareness about emergency contraception among 82 married Muslim women in the reproductive age group. Methods: A cross-sectional study was done in an urban slum area, Raichur where all the Muslim married women in the reproductive age group, attending OPD at UHC, during between August and September 2013 were interviewed using a pre-tested and pre-structured questionnaire. Privacy, anonymity and confidentiality were maintained throughout the process of this study. Results: Out of total 82 Muslim ever married women, majority of them were literate, 63 (76.8%). 50 (61.0%) of women had family size less than or equal to 5. 44 (53.7%) were married at 16-19 years of age and 8 (9.8%) women married between 12-15 years of age which is below legal age of marriage. Maximum total numbers of births were 3-4. Those who wanted male child had births between 5-6. Majority of women 34 (41.5%) had a birth interval of 1 year and 19.5% women had no birth interval. 32 (39.0%) women didn’t use any contraceptive till they completed family. 71 (86.5%) women were aware of all the methods of contraception. Majority of women 30 (36.6%) received information from doctors. Only 11 (13.4%) women were aware of Emergency Contraception. Conclusions: Despite 76.8% literacy and 86.5% of awareness of the various methods of contraception, contraceptive practices were low among women. 32 (39.0%) women didn’t use any contraceptive till they completed family. There is a gap between awareness and practice. Awareness of emergency contraception is quite low among women (13.4%). Emphasis has to be laid on delaying marriage and first pregnancy and education on planning and spacing children and reproductive contraceptive options, especially emergency contraception since all contraceptive methods can have potential failure; the use of emergency contraceptive of plays an important role in preventing unplanned pregnancies. There is a need to improve women's education about EC. The primary health care providers can play a major role in informing their patients about emergency contraception.
Valence, Not Utility, Underlies Reward-Driven Prioritization in Human Vision

Objects associated with reward draw attention and evoke enhanced activity in visual cortex. What is the underlying mechanism? One possibility is that reward's impact on vision is mediated by unique circuitry that modulates sensory processing, selectively increasing the salience of reward-associated stimuli. Alternatively, effects of reward may be part of a more general mechanism that prioritizes the processing of any beneficial object, importantly including stimuli that are associated with the evasion of loss. Here, we test these competing hypotheses by having male and female humans detect naturalistic objects associated with monetary reward, the evasion of equivalent loss, or neither of these. If vision is economically normative, processing of objects associated with reward and evasion of loss should be prioritized relative to neutral stimuli. Results from fMRI and behavioral experiments show that this is not the case: whereas objects associated with reward were better detected and represented in ventral visual cortex, detection and representation of stimuli associated with the evasion of loss were degraded. Representations in parietal cortex reveal a notable exception to this pattern, showing enhanced encoding of both reward- and loss-associated stimuli. Experience-driven visual prioritization can thus be economically irrational, driven by valence rather than objective utility. SIGNIFICANCE STATEMENT Normative economic models propose that gain should have the same value as evasion of equivalent loss. Is human vision rational in this way? Objects associated with reward draw attention and are well represented in visual cortex. This is thought to have evolutionary origins, highlighting objects likely to provide benefit in the future. But benefit can be conferred not only through gain, but also through evasion of loss. Here we demonstrate that the visual system prioritizes real-world objects presented in images of natural scenes only when these objects have been associated with reward, not when they have provided the opportunity to evade financial loss. Visual selection is thus non-normative and economically irrational, driven by valence rather than objective utility.
Best1 Is a Gene Regulated by Nerve Injury and Required for Ca2+-Activated Cl− Current Expression in Axotomized Sensory Neurons

We investigated the molecular determinants of Ca2+-activated chloride current (CaCC) expressed in adult sensory neurons after a nerve injury. Dorsal root ganglia express the transcripts of three gene families known to induce CaCCs in heterologous systems: bestrophin, tweety, and TMEM16. We found with quantitative transcriptional analysis and in situ hybridization that nerve injury induced upregulation of solely bestrophin-1 transcripts in sensory neurons. Gene screening with RNA interference in single neurons demonstrated that mouse Best1 is required for the expression of CaCC in injured sensory neurons. Transfecting injured sensory neurons with bestrophin-1 mutants inhibited endogenous CaCC. Exogenous expression of the fusion protein green fluorescent protein–Bestrophin-1 in naive neurons demonstrated a plasma membrane localization of the protein that generates a CaCC with biophysical and pharmacological properties similar to endogenous CaCC. Our data suggest that Best1 belongs to a group of genes upregulated by nerve injury and supports functional CaCC expression in injured sensory neurons.
Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone lymphoma: a Fondazione Italiana Linfomi phase II study

Rituximab ® provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in patients with SMZL who were either untreated or were splenectomized but had shown disease progression within 1 year after splenectomy. Treatment consisted of six courses of Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-year progression-free survival and overall survival were 54% and 72%, respectively. Toxicity was substantial (grade ≥ 3 neutropenia: 26%; grade ≥ 3 infections: 8%). Of the 15 deaths, two occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, four to secondary neoplasia, one to sepsis, one to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation.
Body and Object Effectors: The Organization of Object Representations in High-Level Visual Cortex Reflects Body–Object Interactions

The principles driving the functional organization of object representations in high-level visual cortex are not yet fully understood. In four human fMRI experiments, we provide evidence that the organization of high-level visual cortex partly reflects the degree to which objects are typically controlled by the body to interact with the world, thereby extending the body's boundaries. Univariate whole-brain analysis showed an overlap between responses to body effectors (e.g., hands, feet, and limbs) and object effectors (e.g., hammers, combs, and tennis rackets) in lateral occipitotemporal cortex (LOTC) and parietal cortex. Region of interest analyses showed that a hand-selective region in left LOTC responded selectively to object effectors relative to a range of noneffector object control conditions (e.g., graspable objects, “act-on” objects, musical instruments). Object ratings showed that the strong response to object effectors in hand-selective LOTC was not due to general action-related object properties shared with these control conditions, such as hand priming, hand grasping, and hand-action centrality. Finally, whole-brain representational similarity analysis revealed that the similarity of multivoxel object response patterns in left lateral occipitotemporal cortex selectively predicted the degree to which objects were rated as being controlled by and extending the body. Together, these results reveal a clustering of body and object effector representations, indicating that the organization of object representations in high-level visual cortex partly reflects how objects relate to the body.
Top-Down Modulation of Auditory-Motor Integration during Speech Production: The Role of Working Memory

Although working memory (WM) is considered as an emergent property of the speech perception and production systems, the role of WM in sensorimotor integration during speech processing is largely unknown. We conducted two event-related potential experiments with female and male young adults to investigate the contribution of WM to the neurobehavioural processing of altered auditory feedback during vocal production. A delayed match-to-sample task that required participants to indicate whether the pitch feedback perturbations they heard during vocalizations in test and sample sequences matched, elicited significantly larger vocal compensations, larger N1 responses in the left middle and superior temporal gyrus, and smaller P2 responses in the left middle and superior temporal gyrus, inferior parietal lobule, somatosensory cortex, right inferior frontal gyrus, and insula compared with a control task that did not require memory retention of the sequence of pitch perturbations. On the other hand, participants who underwent extensive auditory WM training produced suppressed vocal compensations that were correlated with improved auditory WM capacity, and enhanced P2 responses in the left middle frontal gyrus, inferior parietal lobule, right inferior frontal gyrus, and insula that were predicted by pretraining auditory WM capacity. These findings indicate that WM can enhance the perception of voice auditory feedback errors while inhibiting compensatory vocal behavior to prevent voice control from being excessively influenced by auditory feedback. This study provides the first evidence that auditory-motor integration for voice control can be modulated by top-down influences arising from WM, rather than modulated exclusively by bottom-up and automatic processes. SIGNIFICANCE STATEMENT One outstanding question that remains unsolved in speech motor control is how the mismatch between predicted and actual voice auditory feedback is detected and corrected. The present study provides two lines of converging evidence, for the first time, that working memory cannot only enhance the perception of vocal feedback errors but also exert inhibitory control over vocal motor behavior. These findings represent a major advance in our understanding of the top-down modulatory mechanisms that support the detection and correction of prediction-feedback mismatches during sensorimotor control of speech production driven by working memory. Rather than being an exclusively bottom-up and automatic process, auditory-motor integration for voice control can be modulated by top-down influences arising from working memory.