The Efficacy and Safety of Tandem Transplant Versus Single Stem Cell Transplant for Multiple Myeloma Patients: A Systematic Review and Meta-Analysis.

While high-dose therapy and autologous stem cell transplant (ASCT) remain integral to the primary treatment of newly diagnosed transplant-elble multiple myeloma (MM) patients, the challenge of disease progression persists. The primary objective of this meta-analysis is to evaluate the efficacy and safety of tandem ASCT compared to single ASCT. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies comparing tandem ASCT with single ASCT in patients with newly diagnosed MM. We searched PubMed, EMBASE, Cochrane Library, and Clinical Trials databases for studies published up to January 2024. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR), complete response rate (CRR), and treatment-related mortality (TRM). We used a random-effects model to calculate pooled hazard ratios (HRs) and relative risks (RRs) with 95% confidence intervals (CIs). Study quality was assessed using the Cochrane risk of bias tool and Newcastle-Ottawa Scale. Twelve studies involving 5057 patients met the inclusion criteria. Tandem ASCT was associated with a significantly higher CRR compared to single ASCT (HR 1.33, 95% CI 1.03-1.71, I2 = 15%), but no significant differences were observed in PFS (HR 0.75, 95% CI 0.42-1.34, I2 = 14%), OS (HR 0.60, 95% CI 0.33-1.10, I2 = 27%), or the ORR (RR 0.80, 95% CI 0.59-1.08, I2 = 33%). However, tandem ASCT was associated with a significantly higher risk of TRM (RR 1.78, 95% CI 1.00-3.18, I2 = 0%). Tandem ASCT improves the CRR but does not provide significant benefits in terms of PFS, OS, or ORR compared to single ASCT in patients with newly diagnosed MM. Moreover, tandem ASCT is associated with a higher risk of TRM. The decision to pursue tandem ASCT should be made on an individual basis, carefully weighing the potential benefits and risks in light of each patient's unique clinical situation. Future research should focus on identifying patient subgroups most likely to benefit from tandem ASCT and exploring strategies to optimize the efficacy and safety of this approach in the context of novel agent-based therapies.

A meta-analysis of sutureless scleral-fixated intraocular lens versus retropupillary iris claw intraocular lens for the management of aphakia.

This study compared the visual outcomes and complications between sutureless scleral-fixated intraocular lens and iris claw intraocular lens implantation in aphakia without adequate capsule and/or zonule support. Studies comparing the clinical outcomes of scleral-fixated intraocular lens and iris claw intraocular lens implantation published until April 2022 were retrieved from the PubMed, EMBASE, Cochrane Library, and Google Scholar databases. The outcomes included postoperative final visual acuity, surgical time, surgery-induced astigmatism, and complications. The weighted mean difference and odds ratio were calculated. Two randomized controlled trials and five cohort studies, including 244 and 290 eyes in the scleral-fixated intraocular lens group and iris claw group, respectively, were included. Scleral-fixated intraocular lens implantation results in a better postoperative final corrected distance visual acuity compared with iris claw intraocular lens implantation; however, it is more time-consuming. Scleral-fixated intraocular lens implantation seems to have lesser incidences of surgery-induced astigmatism. Furthermore, both procedures have a similar complication rate. Therefore, based on current best evidence, these two procedures should be considered according to patient's conditions.

Proteomic Analysis of Aqueous Humor Proteins in Association with Cataract Risks: Diabetes and Smoking.

Cataracts are one of the most common eye diseases that can cause blindness. Discovering susceptibility factors in the proteome that contribute to cataract development would be helpful in gaining new insights in the molecular mechanisms of the cataract process. We used label-free nanoflow ultra-high-performance liquid chromatography-tandem mass spectrometry to compare aqueous humor protein expressions in cataract patients with different cataract risk factors such as diabetes mellitus (DM) and smoking and in controls (with cataract) without risk exposure. Eight patients with diabetes and who smoked (with double risk factors), five patients with diabetes and five patients who smoked (both with a single risk factor), and nine aged-matched cataract controls patients (non-risk exposure) were enrolled. In total, 136 aqueous humor proteins were identified, of which only alpha-2-Heremans-Schmid (HS)-glycoprotein was considered to be significantly risk-associated because it was differentially expressed in these three groups and exhibited increased expression with increasing risk factors. Significant changes in the aqueous humor level of alpha-2-HS-glycoprotein between DM and control samples and between smoking and control samples were confirmed using ELISA. The alpha-2-HS-glycoprotein, called fetuin-a, could be a potential aqueous biomarker associated with DM and smoking, which were cataract risk factors.

The net clinical benefits of febuxostat versus allopurinol in patients with gout or asymptomatic hyperuricemia - A systematic review and meta-analysis.

BACKGROUND AND AIMS: Systemic reviews and meta-analyses suggest hyperuricemia is a cardiovascular risk factor. The effects of xanthine oxidase inhibitors on cardiac outcomes remain unclear. We assessed the effects of febuxostat and allopurinol on mortality and adverse reactions in adult patients with hyperuricemia. METHODS AND RESULTS: PubMed and EMBASE were searched to retrieve randomized controlled trials of febuxostat and allopurinol from January 2005 to July 2018. The meta-analysis consisted of 13 randomized controlled trials with a combined sample size of 13,539 patients. Febuxostat vs. allopurinol was not associated with an increased risk of cardiac-related mortality in the overall population (OR: 0.72, 95% CI: 0.24-2.13, P = 0.55). Regarding adverse skin reactions, the patients receiving febuxostat had significantly fewer adverse skin reactions than those receiving allopurinol treatment (OR: 0.50, 95% CI: 0.30-085, P = 0.01). Compared with allopurinol, febuxostat was associated with an improved safety outcome of cardiac-related mortality and adverse skin reactions (OR: 0.72, 95% CI: 0.55-0.96, P = 0.02). The net clinical outcome, composite of incident gout and the safety outcome, was not different significantly in the patients receiving febuxostat or allopurinol (OR: 1.04, 95% CI: 0.76-0.1.42, P = 0.79). In sensitivity analyses, a borderline significance was found in the patients randomized to febuxostat vs. allopurinol regarding cardiac-related mortality (OR: 1.29, 95% CI: 1.00-1.67, P = 0.05) after the CARES study was included. CONCLUSION: Febuxostat vs. allopurinol was associated with the improved safety outcome and have comparable mortality and net clinical outcome in patients with hyperuricemia. REGISTRATION NUMBER: PROSPERO(CRD42018091657).

Identification of preoptic sleep neurons using retrograde labelling and gene profiling.

In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep. However, the sleep-active neurons are spatially intermingled with wake-active neurons, making it difficult to target the sleep neurons specifically for circuit analysis. Here we identify a population of preoptic area sleep neurons on the basis of their projection target and discover their molecular markers. Using a lentivirus expressing channelrhodopsin-2 or a light-activated chloride channel for retrograde labelling, bidirectional optogenetic manipulation, and optrode recording, we show that the preoptic area GABAergic neurons projecting to the tuberomammillary nucleus are both sleep active and sleep promoting. Furthermore, translating ribosome affinity purification and single-cell RNA sequencing identify candidate markers for these neurons, and optogenetic and pharmacogenetic manipulations demonstrate that several peptide markers (cholecystokinin, corticotropin-releasing hormone, and tachykinin 1) label sleep-promoting neurons. Together, these findings provide easy genetic access to sleep-promoting preoptic area neurons and a valuable entry point for dissecting the sleep control circuit.

Cell type-specific long-range connections of basal forebrain circuit.

The basal forebrain (BF) plays key roles in multiple brain functions, including sleep-wake regulation, attention, and learning/memory, but the long-range connections mediating these functions remain poorly characterized. Here we performed whole-brain mapping of both inputs and outputs of four BF cell types - cholinergic, glutamatergic, and parvalbumin-positive (PV+) and somatostatin-positive (SOM+) GABAergic neurons - in the mouse brain. Using rabies virus -mediated monosynaptic retrograde tracing to label the inputs and adeno-associated virus to trace axonal projections, we identified numerous brain areas connected to the BF. The inputs to different cell types were qualitatively similar, but the output projections showed marked differences. The connections to glutamatergic and SOM+ neurons were strongly reciprocal, while those to cholinergic and PV+ neurons were more unidirectional. These results reveal the long-range wiring diagram of the BF circuit with highly convergent inputs and divergent outputs and point to both functional commonality and specialization of different BF cell types.

Novel gas chromatographic detector utilizing the localized surface plasmon resonance of a gold nanoparticle monolayer inside a glass capillary.

This paper presents the design, assembly, and evaluation of a novel gas chromatographic detector intended to measure the absorbance of the localized surface plasmon resonance (LSPR) of a gold nanoparticle monolayer in response to eluted samples from a capillary column. Gold nanoparticles were chemically immobilized on the inner wall of a glass capillary (i.d. 0.8 mm, length = 5-15 cm). The eluted samples flowed through the glass capillary and were adsorbed onto a gold nanoparticle surface, which resulted in changes in the LSPR absorbance. The LSPR probing light source used a green light-emitting diode (LED; λ(center) = 520 nm), and the light traveled through the glass wall of the capillary with multiple total reflections. The changes in the light intensity were measured by a photodiode at the rear of the glass capillary. The sensitivity of this detector can be improved by using a longer spiral glass capillary. The detector is more sensitive when operated at a lower temperature and at a slower carrier velocity. The calibration lines of 8 preliminary test compounds were all linear (R(2) > 0.99). The detection limits (3σ) ranged from 22 ng (n-butanol) to 174 ng (2-pentanone) depending on the volatility of the chemicals and the affinity to the citrate lignads attached to the gold nanoparticle surface. This detector consumed a very low amount of energy and could be operated with an air carrier gas, which makes this detector a promising option for portable GC or µGC.

A novel Gαs-binding protein, Gas-2 like 2, facilitates the signaling of the A2A adenosine receptor.

The A2A adenosine receptor (A2AR) is a G-protein-coupled receptor that contains a long cytoplasmic carboxyl terminus (A2AR-C). We report here that Gas-2 like 2 (G2L2) is a new interacting partner of A2AR-C. The interaction between A2AR and G2L2 was verified by GST pull-down, co-immunoprecipitation, immunocytochemical staining, and fluorescence resonance energy transfer. Expression of G2L2 increased the intracellular cAMP content evoked by A2AR in an A2AR-C-dependent manner. Immunoprecipitation and pull-down assays demonstrated that G2L2 selectively bound to A2AR-C and the inactive form of Gαs to facilitate the recruitment of the trimeric G protein complex to the proximal position of A2AR for efficient activation. Collectively, G2L2 is a new effector that controls the action of A2AR by modulating its ability to regulate the Gαs-mediated cAMP contents.

Regulation of feedback between protein kinase A and the proteasome system worsens Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6(S120A)) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6(S120D)) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis.

Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease.

Adenosine monophosphate-activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.