Onset Of Response Research Articles

A randomized, double-blind, placebo-controlled study of tamibarotene/azacitidine versus placebo/azacitidine in newly diagnosed adult patients selected for RARA+ HR-MDS (SELECT-MDS-1).

TPS7075 Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). Biologically targeted therapy with tamibarotene, an oral selective RARα agonist, has potential to provide clinical benefit for RARA+ HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA+ R/R HR-MDS patients treated with tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) showed high complete response rates (CR) with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/aza was generally well tolerated with no increase in myelosuppression compared to aza alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of tamibarotene/aza in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Methods: This Phase 3, multi-center, randomized, double-blind, placebo-controlled study will compare activity of tamibarotene/aza to placebo/aza in RARA+ patients with ND HR-MDS. The primary objective is to characterize and compare the CR rate of tamibarotene/aza vs placebo/aza, with secondary objectives to characterize ORR, EFS, OS, transfusion independence rate, time to and duration of initial and complete responses, and safety. Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms, with a one-sided alpha of 0.025. Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a blast count > 5% at study entry. Patients suitable for transplant at screening, or with prior treatment for MDS with any HMA, chemotherapy or transplant are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per modified IWG MDS criteria (Cheson 2006). The SELECT-MDS-1 trial opened in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe. Clinical trial information: NCT04797780.

Bimekizumab for the Treatment of Psoriasis: A Review of the Current Knowledge.

Bimekizumab, a novel humanized monoclonal IgG1 antibody that neutralizes both IL-17A and IL-17F, was recently approved the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Bimekizumab represents the latest anti IL-17 treatment available for the management of moderate to severe psoriasis. Bimekizumab safety and efficacy profiles were evaluated in four Phase III clinical trials, which evaluated bimekizumab versus placebo and ustekinumab (BE VIVID), versus placebo (BE READY), versus adalimumab (BE SURE), and versus secukinumab (BE RADIANT). Overall, bimekizumab displayed promising results in terms of both efficacy and safety, allowing reach PASI90 and PASI100 in short time (as early as week 4) and maintain it in the long term (52 weeks), with acceptable safety profile. Also, bimekizumab showed a rapid onset of response and a higher efficacy when compared to adalimumab, ustekinumab and secukinumab, with comparable safety profile. Herein, we carried out a comprehensive literature review of the available literature data about bimekizumab in the treatment of moderate to severe psoriasis.

Role of the Microbiota in Lung Cancer: Insights on Prevention and Treatment.

The microbiota is increasingly recognized as a critical player in cancer onset and progression and response to cancer chemotherapy treatment. In recent years, several preclinical and clinical studies have evidenced the involvement of microbiota in lung cancer, one of the world’s deadliest cancers. However, the mechanisms by which the microbiota can impact this type of cancer and patient survival and response to treatments remain poorly investigated. In this review, the peculiarities of the gut and lung microbial ecosystems have been highlighted, and recent findings illustrating the possible mechanisms underlying the microbiota–lung cancer interaction and the host immune response have been discussed. In addition, the mucosal immune system has been identified as a crucial communication frame to ease interactive dynamics between the immune system and the microbiota. Finally, the use of specific next-generation intestinal probiotic strains in counteracting airway diseases has been evaluated. We believe that restoring homeostasis and the balance of bacterial microflora should become part of the routine of integrated cancer interventions, using probiotics, prebiotics, and postbiotics, and promoting a healthy diet and lifestyle.

Paucigranulocytic Asthma: Potential Pathogenetic Mechanisms, Clinical Features and Therapeutic Management.

Asthma is a heterogeneous disease usually characterized by chronic airway inflammation, in which several phenotypes have been described, related to the age of onset, symptoms, inflammatory characteristics and treatment response. The identification of the inflammatory phenotype in asthma is very useful, since it allows for both the recognition of the asthmatic triggering factor as well as the optimization of treatment The paucigranulocytic phenotype of asthma (PGA) is characterized by sputum eosinophil levels <1–3% and sputum neutrophil levels < 60%. The precise characteristics and the pathobiology of PGA are not fully understood, and, in some cases, it seems to represent a previous eosinophilic phenotype with a good response to anti-inflammatory treatment. However, many patients with PGA remain uncontrolled and experience asthmatic symptoms and exacerbations, irrespective of the low grade of airway inflammation. This observation leads to the hypothesis that PGA might also be either a special phenotype driven by different kinds of cells, such as macrophages or mast cells, or a non-inflammatory phenotype with a low grade of eosinophilic inflammation. In this review, we aim to describe the special characteristics of PGA and the potential therapeutic interventions that could be offered to these patients.

Altered performance monitoring in Tourette Syndrome: an MEG investigation

The error-related negativity (ERN) is an event-related potential component indexing processes of performance monitoring during simple stimulus-response tasks: the ERN is typically enhanced for error processing and conflicting response representations. Investigations in healthy participants and different patient groups have linked the ERN to the dopamine system and to prefrontal information processing. As in patients with Tourette Syndrome (TS) both dopamine release and prefrontal information processing are impaired, we hypothesized that performance monitoring would be altered, which was investigated with magnetencephalography (MEG). We examined performance monitoring in TS patients by assessing the magnetic equivalent of the ERN (mERN). The mERN was investigated in tic-free trials of eight adult, unmedicated TS patients without clinically significant comorbidity and ten matched healthy controls while performing a Go/NoGo task in selected frontocentral channels. The analysis of the response-related amplitudes of the event-related magnetic field showed that TS patients, in contrast to controls, did not show earlier amplitude modulation (between 70 and 105 ms after response onset) depending on response type (errors or correct responses). In both groups significant mERN amplitudes in the time-window between 105 and 160 ms after response onset were detected thus pointing at only later error processing in TS patients. In TS patients, early error-related processing might be affected by an enhanced motor control triggered by a conflict between the targeted high task performance and tic suppression. TS patients seem to tend to initially process all responses as erroneous responses.

Adaptive immune defense prevents Bartonella persistence upon trans-placental transmission.

Vertical transmission of Bartonella infection has been reported for several mammalian species including mice and humans. Accordingly, it is commonly held that acquired immunological tolerance contributes critically to the high prevalence of Bartonellae in wild-ranging rodent populations. Here we studied an experimental model of Bartonella infection in mice to assess the impact of maternal and newborn immune defense on vertical transmission and bacterial persistence in the offspring, respectively. Congenital infection was frequently observed in B cell-deficient mothers but not in immunocompetent dams, which correlated with a rapid onset of an antibacterial antibody response in infected WT animals. Intriguingly, B cell-deficient offspring with congenital infection exhibited long-term bacteremia whereas B cell-sufficient offspring cleared bacteremia within a few weeks after birth. Clearance of congenital Bartonella infection resulted in immunity against bacterial rechallenge, with the animals mounting Bartonella-neutralizing antibody responses of normal magnitude. These observations reveal a key role for humoral immune defense by the mother and offspring in preventing and eliminating vertical transmission. Moreover, congenital Bartonella infection does not induce humoral immune tolerance but results in anti-bacterial immunity, questioning the contribution of neonatal tolerance to Bartonella prevalence in wild-ranging rodents.

Acoustic change complex using short duration stimuli in normal hearing children: temporal resolution and frequency discrimination

Objective Acoustic Change Complex (ACC) is a cortical auditory evoked potential elicited in response to a change in an ongoing sound. Since it is supposed to reflect auditory discrimination at the cortical level, recording of this potential has recently gained much attention. From a technical standpoint, the stimulus used should be long enough to accommodate the needed change. This research addresses the development and standardization of short duration tonal stimuli which can be implemented in most of the Evoked Potential (EP) equipment used in regular Audiology clinics. Methods Short duration tonal stimuli (500 msec.) were generated and edited using Audacity software. Temporal change was done using gap-in-tones stimuli (6, 10, 30 and 50 msec. in 1000 Hz tone). Frequency change was represented by frequency pairs (2%, 4%, 10% and 25% change from 1000 Hz base frequency). The developed stimuli were then used to generate ACC potential in 41 normal hearing children ranging in age from 2 to 10 years. A comparison was held between ACC response recorded using the different stimuli in reference to percent identifiability, morphology, latency and amplitude measures. Results Gap-in-tones at 10 msec. and 4% frequency change could elicit ACC response in 100% of subjects. ACC had the same morphology of the onset response in the majority of subjects, with longer latency and smaller amplitude. ACC amplitude was consistently affected by magnitude of change. Conclusion ACC was successfully recorded in 100% of normal hearing children using the developed short duration tonal stimuli for temporal change (10 msec.) and frequency change (4%). These stimuli can be uploaded in clinical EP equipment. ACC amplitude could be a better indicator of cortical discrimination compared to latency.

Kinetics of the inflammatory response during experimental Babesia rossi infection of beagle dogs

Babesia rossi causes severe morbidity and mortality in dogs in sub-Saharan Africa, and the complications associated with this disease are likely caused by an unfocused, excessive inflammatory response. During this experimental B. rossi study we investigated inflammatory marker and cytokine kinetics during infection and after treatment. We aimed to determine whether infectious dose and treatment would influence the progression of the inflammatory response and clinical disease. Six healthy male beagle dogs formed the study population, one was used to raise the infectious inoculum, three were administered a high B. rossi infectious dose (HD group) and two a low infectious dose (LD group). Clinical examination, complete blood count (CBC) and C-reactive protein (CRP) were determined daily. Cytokines were quantified on stored plasma collected during the study, using a canine specific cytokine magnetic bead panel (Milliplex©). The experiment was terminated and treatment administered when predetermined experimental or humane endpoints were reached. Parasitemia occurred on day 1 and 3 in the HD and LD groups respectively. The rate of increase in parasitemia in the HD group was significantly faster than that seen in the LD group. Significant differences were found in heart rate, blood pressure, interferon gamma (INFγ), keratinocyte chemoattractant (KC), INFγ-induced protein 10 (IP10), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP1), tumor necrosis factor alpha (TNFα), interleukin 2 (IL-2), IL-6, IL-7, IL-8, IL-10 IL-15, IL-18, CRP, neutrophils and monocytes between groups at multiple time points during the course of the infection. Our findings suggest that the initiation of inflammation occurs before the onset of clinical disease in B. rossi infection and infectious dose influences the onset of the inflammatory response. Treatment enhances the inflammatory response in the immediate post-treatment period which may contribute to disease associated complications. Finally, we found that there is an imbalance in pro/anti-inflammatory cytokine concentrations during infection which may promote parasite replication.

Ductile fracture modeling using the modified Mohr–Coulomb model coupled with a softening law for an ASTM A285 steel

Ductile fracture is one relevant failure mechanism in pressurized metallic components such as pressure vessels and pipelines. This work describes a framework to model ductile fracture based on phenomenological critical local strain criterion coupled with softening law rule to predict the onset of ductile fracture and tearing response in typical geometries extracted from an ASTM A285 steel. Overall, the numerical predicted load vs. displacement curves are in good agreement with measured data for all samples. Detailed numerical analyses are also performed to investigate the strain capacity of defected pipes under internal pressure and axial loading.

Comprehensive lipidomics of lupus-prone mice using LC-MS/MS identifies the reduction of palmitoylethanolamide that suppresses TLR9-mediated inflammation.

Lipid mediators are known to play crucial roles not only in the onset of the inflammatory response but also in the induction of resolution of inflammation. Here, we report that palmitoylethanolamide (PEA), an endogenous N-acylethanolamine, can suppress the inflammation induced by Toll-like receptor (TLR) signaling both in vitro and in vivo. PEA was found to be significantly reduced in the serum and spleen of lupus-prone MRL/lpr mice analyzed by lipidomics. PEA suppressed pro-inflammatory cytokine production in a mouse macrophage cell line stimulated with TLR ligands such as lipopolysaccharide, peptidoglycan, poly (I:C), imiquimod, and CpG-ODN. PEA also inhibited both mRNA and protein levels of IL-6 in bone marrow-derived dendritic cells (BMDCs) and B cells stimulated with CpG-ODN. Augmentation of cell surface CD86 and CD40 on BMDCs and B cells, IgM production, and cell proliferation of B cells in response to CpG-ODN were attenuated by PEA. Moreover, PEA treatment significantly reduced mortality and serum IL-6 levels in mice injected with CpG-ODN plus D-galactosamine. Taken together, PEA ameliorates inflammation induced by TLR signaling, which could be a novel therapeutic target for inflammatory disorders.

Probing the Drug Dynamics of Chemotherapeutics Using Metasurface-Enhanced Infrared Reflection Spectroscopy of Live Cells.

Infrared spectroscopy has drawn considerable interest in biological applications, but the measurement of live cells is impeded by the attenuation of infrared light in water. Metasurface-enhanced infrared reflection spectroscopy (MEIRS) had been shown to mitigate the problem, enhance the cellular infrared signal through surface-enhanced infrared absorption, and encode the cellular vibrational signatures in the reflectance spectrum at the same time. In this study, we used MEIRS to study the dynamic response of live cancer cells to a newly developed chemotherapeutic metal complex with distinct modes of action (MoAs): tricarbonyl rhenium isonitrile polypyridyl (TRIP). MEIRS measurements demonstrated that administering TRIP resulted in long-term (several hours) reduction in protein, lipid, and overall refractive index signals, and in short-term (tens of minutes) increase in these signals, consistent with the induction of endoplasmic reticulum stress. The unique tricarbonyl IR signature of TRIP in the bioorthogonal spectral window was monitored in real time, and was used as an infrared tag to detect the precise drug delivery time that was shown to be closely correlated with the onset of the phenotypic response. These results demonstrate that MEIRS is an effective label-free real-time cellular assay capable of detecting and interpreting the early phenotypic responses of cells to IR-tagged chemotherapeutics.

The Maturation of the Acoustic Change Complex in Response to Iterated Ripple Noise in 'Normal'-Hearing Infants, Toddlers, and Adults.

Infants and toddlers are still being evaluated for their hearing sensitivity but not their auditory-processing skills. Iterated rippled noise (IRN) stimuli require the auditory system to utilize the temporal periodicity and autocorrelate the iterations to perceive pitch. This study investigated the acoustic change complex (ACC) elicited by IRN in "normal"-hearing infants, toddlers, and adults to determine the maturation of cortical processing of IRN stimuli. Cortical responses to filtered white noise (onset) concatenated with IRN stimuli (d = 10 milliseconds, gain = 0.7 dB: 4-32 iterations) were recorded in quiet, alert participants. Participants included 25 infants (2.5-15 months), 27 toddlers (22-59 months), and 8 adults (19-25 years) with "normal" hearing sensitivity. Cortical auditory-evoked responses were recorded for each participant, including the onset response to the noise and an ACC to the transition from noise to IRN. Group differences were assessed using repeated-measures analyses of variance. Most infants had a replicable onset (P) response, while only about half had a measurable ACC (PACC) response to the high-saliency IRN condition. Most toddlers had onset responses and showed a P-NACC response to the IRN16 and IRN32 conditions. Most of the toddler group had responses present to the onset and showed a P-NACC response to all IRN conditions. Toddlers and adults showed similar P-NACC amplitudes; however, adults showed an increase in N1ACC amplitude with increase in IRN iterations (i.e., increased salience). While cortical responses to the percept of sound as determined by the onset response (P) to a stimulus are present in most infants, ACC responses to IRN stimuli are not mature in infancy. Most toddlers as young as 22 months, however, exhibited ACC responses to the IRN stimuli even when the pitch saliency was low (e.g., IRN4). The findings of the current study have implications for future research when investigating maturational effects on ACC and the optimal choice of stimuli.

Intracranial Cerebrovascular Reactivity by Traditional and Novel Methods in Young, Middle, and Old Aged Healthy Males and Females

ObjectiveLower cerebrovascular reactivity (CVR) to hypercapnia is associated with increased risk of age‐related cognitive decline and all‐cause mortality. Despite the important clinical implications of CVR, evidence of the physiological changes across the healthy adult lifespan is conflicting, with limited findings in females. The aim of this study was to assess the effect of age and sex on CVR. We hypothesized: 1) CVR to be lower in middle‐aged and older compared to young adults, and 2) a higher CVR in young females compared with young males, and a higher CVR in older males than older females.MethodsYoung (n=25, 12 female, age 27±1.5y), middle‐age (n=31, 18 female, age 54±7.3y) and older healthy participants (n=20, 10 female, age 70±2.5y) completed CVR via inhalation of 5% carbon dioxide (CO2) for 5 minutes. Traditional CVR was characterized by the peak middle cerebral artery velocity (MCAv) response per mmHg increase in end‐tidal CO2 (traditional cm/s‐1mmHg), and using a novel mono‐exponential model to characterize the dynamic onset response of the MCAv. Independent samples ANOVA was used to compare main and interaction effects of age and sex.ResultsTraditional CVR was not different between young, middle and older groups (2.0±0.7 vs 1.8±0.9 vs 1.9±0.9 cm/s‐1mmHg; P=0.102). Dynamic onset (novel) responses revealed the time constant of the MCAv response was significantly slower in older and middle‐aged compared to young adults (29±16 vs 27±20 vs 14±9 seconds, P=0.03). No effects of sex were observed for traditional or novel CVR (P≥0.14), but young females had a higher baseline MCAv than young males (70.8 vs 78.6 cm/s‐1P=0.04), which was not observed in middle and older age adults.ConclusionsCVR is preserved in ageing adults, but the speed of the MCAv response is blunted in older and middle‐aged adults compared to young adults. Utilizing dynamic onset responses reveal underlying differences in cerebral regulation with healthy ageing that were not detected by traditional methods.

Light Chain Cast Nephropathy in Multiple Myeloma: Prevalence, Impact and Management Challenges.

“Cast nephropathy” (CN) is a pathological feature of myeloma kidney, also seen to a lesser extent in the context of severe nephrotic syndrome from non-haematological diseases. The name relates to obstruction of distal tubules by “casts” of luminal proteins concentrated by intensive water reabsorption resulting from dehydration or high-dose diuretics. Filtered proteins form complexes with endogenous tubular Tamm-Horsfall glycoprotein. The resulting gel further slows or stops luminal flow upon complete obstruction of distal convoluted tubules and collecting ducts. Thus, a tubular obstructive form of acute kidney injury (AKI) is a common consequence of CN. The pathogenesis of CN will be reviewed in light of recent advances in the understanding of monoclonal disorders of B lymphocytes, leading to the release of immunoglobulin components (free light chains, FLC) into the bloodstream and their filtration across the glomerular basement membrane. Treatment aiming at reduction of the circulating burden of FLC may help recovery of renal function in a fraction of these patients, besides filling the void between the onset of AKI, histopathological diagnosis, and full response to pharmacologic treatment.

Bacteria‐Derived Hypoxanthine Accelerates Gastrointestinal Transit

Irritable bowel syndrome is a globally prevalent disorder categorized into constipation, diarrhea or mixed (IBS‐C, IBD‐D, IBS‐M) based on the predominant stool form/frequency. While the gut microbiome is recognized as an important factor underlying the pathophysiology of IBS, the specific mechanisms remain an area of active investigation. In our recent longitudinal multi‐omics study in IBS patients, we found bacteria‐derived hypoxanthine was significantly decreased in stool from IBS‐C patients. The aim of this study was to determine if IBS‐C relevant molecular pathways are affected by hypoxanthine. We hypothesized that hypoxanthine acts on enterochromaffin (EC) cells to stimulate serotonin (5‐HT) release, where 5‐HT is an important determinant of gastrointestinal (GI) transit time. We used Ca2+ imaging in QGP cells (EC model), T84 cells (colonocyte model), primary cells and organoids from NeuroD1‐cre;GCaMP5‐tdTomato mice [NeuroD1 is a marker for enteroendocrine cells (EECs) which express calcium indicator GCaMP in these mice] in the absence or presence of receptor antagonists, and in ex vivo colon preparations with intact innervation from E2aCre:GCaMP6s mice (GCaMP is expressed in neuronal and non‐neuronal cells), to test the effect of hypoxanthine. The physiologic relevance of hypoxanthine signaling was assessed by measuring whole gut transit time. We found hypoxanthine increased Ca2+ influx in QGP cells [using Cal520 (qualitative) and Fura‐2AM (quantitative)], primary EECs and EECs within organoids (previous research showed that the majority of these EECs are EC cells), but not in T84 cells. Hypoxanthine‐evoked Ca2+ response was absent in Ca2+‐free medium (n=6‐8, t‐test, P&lt;0.0001), inhibited by Gαi/o‐GPCR antagonist (pertussis toxin; n=8‐14, t‐test, P&lt;0.01)), Transient Receptor Potential Cation Channel Subfamily C Member 4 (TRPC4) antagonist (ML204; n=14‐15, t‐test, P&lt;0.0001) and TRPC4 siRNA (n=5‐21, t‐test, P&lt;0.01), and was accompanied by increased 5‐HT release (measured using 5‐HT biosensor). In ex vivo experiments, luminal application of hypoxanthine activated a subset of epithelial cells (likely EC cells) followed by subsets of neurons (latency to response onset, n=4, Mann‐Whitney, P&lt;0.0001), as well as movement of the imaging field, which indicates smooth muscle contraction/relaxation. Our in vitro findings were confirmed by in vivo experiments showing that germ‐free mice colonized with hypoxanthine‐producing bacteria had faster whole gut transit and higher stool 5‐HT level compared to hypoxanthine‐consuming bacteria (n=7‐8, t‐test, P&lt;0.05). In summary, hypoxanthine increases Ca2+ influx specifically in EC cells by activating a signaling cascade involving a Gαi/o‐GPCR and TRPC4 channels, which results in 5‐HT release. The delay in activation of myenteric neurons and motor activity suggests that EC cell 5‐HT release likely induces neurogenic motor patterns and may underlie the shorter GI transit time seen with increased bacterial hypoxanthine production. While the current empirically designed probiotics have proven ineffective in IBS, our findings will allow development of novel mechanism‐based probiotic therapies for IBS‐C using hypoxanthine‐producing bacteria.

FORMULATION DEVELOPMENT AND EVALUATION OF FAST DISSOLVING TABLETS OF TORSEMIDE

Hypertension is a chronic disease that is characterized by a persistently high blood pressure. It can cause strokes, myocardial infarctions, heart failure, and chronic kidney failure if not treated properly. An effort has been made to develop a fast dissolving tablet containing torsemide, which is used in the treatment of hypertension, in enhancing the onset of action, therapeutic response, patient acceptance, and ease of access. Torsemide fast dissolving tablets (FDTs) were prepared by direct compression method using different ratios of super-disintegrants. The prepared tablets were subjected to both pre and post evaluation parameters including Fourier Transform Infrared spectroscopy (FT-IR), Differential Scanning Calorimetry, Micromeritics properties, Hardness, weight variation, friability, disintegration time, wetting time, water absorption ratio and in-vitro dissolution studies. FTIR studies showed that the drug and excipients are compatible. According to the micromeritics analysis, all formulations had acceptable to good flow ability. Tablet hardness and friability indicated that the prepared formulations were having good mechanical strength. The formulation F27 which was prepared by using of super-disintegrant Crospovidone gave the good results for tablet disintegration, wetting time, and water absorption ratio and in-vitro dissolution.

P555. Early and Steady-State Visual Neuro-Oscillations Across the Psychosis Spectrum

Early visual neuro-oscillations are promising translational biomarkers. This study comprehensively examines visual EEG onset and steady-state responses in a large well characterized trans-diagnostic psychosis sample (n=831) by DSM and by biologically derived psychosis sub-groups (B-SNIP Biotypes).

Potential efficacy of hepatic arterial infusion chemotherapy using gemcitabine, cisplatin, and 5-fluorouracil for intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, as the resectability rate is low due to its diagnosis at a late/advanced stage. Moreover, most patients with resected ICC eventually relapse. Hepatic arterial infusion chemotherapy (HAIC) has been indicated only by a few reports to be effective in patients with advanced ICC; thus, its efficacy for these patients remains unclear. This study aimed to evaluate the efficacy of HAIC using gemcitabine, cisplatin, and 5-fluorouracil in patients with advanced ICC. A total of 18 patients who underwent HAIC were retrospectively investigated. The patients received gemcitabine, cisplatin, and 5-fluorouracil through one artery. In patients who received gemcitabine plus cisplatin (n = 10), the response and disease control rates were 0% and 80.0%, respectively; the median overall survival (OS) and progression-free survival (PFS) after treatment initiation were 6.3 and 3.7 months, respectively. In patients who never received chemotherapy (n = 8), the response and disease control rates were 37.5% and 75%, respectively; the median OS and PFS were 20.6 and 8.1 months, respectively. Moreover, we compared the patients who received HAIC using gemcitabine, cisplatin, and 5-fluorouracil to patients whose tumors were refractory to systemic gemcitabine and cisplatin therapy. The OS of the patients who received HAIC was better than that of the patients who received standard chemotherapy cohort since the gemcitabine plus cisplatin combination therapy-refractory response and disease onset (P = 0.045, 0.006). HAIC using gemcitabine, cisplatin, and 5-fluorouracil may be effective as a therapeutic option for patients with advanced ICC.

A TMS-induced cortical silent period delays the contralateral limb for bimanual symmetrical movements and the reaction time delay is reduced on startle trials.

Bimanual actions are typically initiated and executed in a temporally synchronous manner, likely due to planning bilateral commands as a single motor "program." Applying high-intensity transcranial magnetic stimulation (TMS) to the motor cortex can result in a contralateral cortical silent period that delays reaction time (RT), if timed to coincide with the final motor output stage. The current study examined the impact of a unilateral TMS silent period on the RT and interlimb timing of bilateral wrist extension. In addition, because a loud, startling acoustic stimulus (SAS) can result in the involuntary release of preprogrammed actions via increased reticulospinal activation, it was of interest whether startle-induced speeding of response initiation would moderate the impact of the TMS-induced RT delay. Participants performed blocks of unilateral and bilateral wrist extension in response to an acoustic (82 dB) go-signal. On selected trials, either TMS was applied to the left motor cortex 70 ms before the expected EMG response onset, a SAS (120 dB) replaced the go-signal, or both TMS and SAS were delivered. Results showed that TMS led to a significant RT delay in the right limb during both unimanual and bimanual extension but had no impact on the left limb initiation. In addition, the magnitude of the right limb RT delay was smaller when the response was triggered by a SAS. These results imply that preplanned bimanually synchronous movements are susceptible to lateralized dissociation late into the cortical motor output stage and movements triggered by startle involve increased reticulospinal output.NEW & NOTEWORTHY Bilateral responses are typically planned synchronously and performed symmetrically. Here, we show that delaying the initiation of one limb using transcranial magnetic stimulation (TMS) to produce a cortical silent period does not impact the other limb during bimanual movements. Also, the TMS-induced delay is reduced when a startling acoustic stimulus (SAS) triggers the movement. These results confirm that tightly coupled bilateral responses can be dissociated by contralateral TMS- and SAS-triggered responses involve greater reticulospinal output.

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

Waldenström Macroglobulinemia (WM) is an indolent lymphoplasmacytic lymphoma, characterized by the production of excess immunoglobulin M monoclonal protein. WM belongs to the spectrum of IgM gammopathies, ranging from asymptomatic IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), through IgM-related disorders and asymptomatic WM to symptomatic WM. In recent years, its complex genomic and transcriptomic landscape has been extensively explored, hereby elucidating the biological mechanisms underlying disease onset, progression and therapy response. An increasing number of mutations, cytogenetic abnormalities, and molecular signatures have been described that have diagnostic, phenotype defining or prognostic implications. Moreover, cell-free nucleic acid biomarkers are increasingly being investigated, benefiting the patient in a minimally invasive way. This review aims to provide an extensive overview of molecular biomarkers in WM and IgM-MGUS, considering current shortcomings, as well as potential future applications in a precision medicine approach.