Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer

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Phase I Dose-Escalation Study of SCB01A,a Microtubule Inhibitor with Vascular Disrupting Activity,in Patients with Advanced Solid Tumors

Lessons Learned

• SCB01A is a novel microtubule inhibitor with vascular disrupting activity.
• This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.
• SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity.

BackgroundSCB01A, a novel microtubule inhibitor, has vascular disrupting activity.MethodsIn this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m² to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints.ResultsTreatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m² cohort; grade 3 gastric hemorrhage in the 6.5 mg/m² cohort; grade 2 thromboembolic event in the 24 mg/m² cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m² cohort. The MTD was 24 mg/m², and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro.ConclusionThe MTD of SCB01A was 24 mg/m² every 21 days; it is safe and tolerable in patients with solid tumors.     

Interrelationships between Cellular Density,Mosaic Patterning,and Dendritic Coverage of VGluT3 Amacrine Cells

Amacrine cells of the retina are conspicuously variable in their morphologies, their population demographics, and their ensuing functions. Vesicular glutamate transporter 3 (VGluT3) amacrine cells are a recently characterized type of amacrine cell exhibiting local dendritic autonomy. The present analysis has examined three features of this VGluT3 population, including their density, local distribution, and dendritic spread, to discern the extent to which these are interrelated, using male and female mice. We first demonstrate that Bax-mediated cell death transforms the mosaic of VGluT3 cells from a random distribution into a regular mosaic. We subsequently examine the relationship between cell density and mosaic regularity across recombinant inbred strains of mice, finding that, although both traits vary across the strains, they exhibit minimal covariation. Other genetic determinants must therefore contribute independently to final cell number and to mosaic order. Using a conditional KO approach, we further demonstrate that Bax acts via the bipolar cell population, rather than cell-intrinsically, to control VGluT3 cell number. Finally, we consider the relationship between the dendritic arbors of single VGluT3 cells and the distribution of their homotypic neighbors. Dendritic field area was found to be independent of Voronoi domain area, while dendritic coverage of single cells was not conserved, simply increasing with the size of the dendritic field. Bax-KO retinas exhibited a threefold increase in dendritic coverage. Each cell, however, contributed less dendrites at each depth within the plexus, intermingling their processes with those of neighboring cells to approximate a constant volumetric density, yielding a uniformity in process coverage across the population.SIGNIFICANCE STATEMENT Different types of retinal neuron spread their processes across the surface of the retina to achieve a degree of dendritic coverage that is characteristic of each type. Many of these types achieve a constant coverage by varying their dendritic field area inversely with the local density of like-type neighbors. Here we report a population of retinal amacrine cells that do not develop dendritic arbors in relation to the spatial positioning of such homotypic neighbors; rather, this cell type modulates the extent of its dendritic branching when faced with a variable number of overlapping dendritic fields to approximate a uniformity in dendritic density across the retina.     

B超引导下经皮穿刺囊内注射铝溶液治疗肾囊肿

在 B 超引导下经皮穿刺囊内注射铝溶液治疗肾囊肿72例89个囊肿结果:消失48个,有效36个,总有效率94%。随访3个月至2年未见复发。其方法安全、简便、无副作用。并对铝溶液作用机制进行初步探讨。     

Mechanisms mediating the brain stem control of somatosensory transmission in the dorsal horn of the cat's spinal cord: an intracellular analysis

Summary The effect of brainstem stimulation was studied on neurones recorded intracellularly in the superficial and deeper laminae of the lumbosacral dorsal horn of the spinal cord in anaesthetised cats. Stimulation in the nucleus locus coeruleus (LC) produced a hyperpolarisation in 4/13 multireceptive neurones and produced a biphasic action consisting of a hyperpolarisation which was followed by a depolarisation in 3/13 neurones. These actions were produced irrespective of whether the multireceptive neurone was located in the superficial or deeper laminae of the dorsal horn. Stimulation failed to produce postsynaptic potentials in the remaining 6/13 multireceptive neurones. The amplitude of hyperpolarisation was increased by the passage of depolarising pulses through the recording microelectrode and decreased by hyperpolarising pulses. Stimulation in other brainstem areas such as, the lateral (FTL), paralemniscal (FTP) and central (FTC) divisions of the tegmental field and the nuclei raphe magnus (NRM) and reticularis magnocellularis (RMc) also hyperpolarised neurones in the dorsal horn. The polarity of hyperpolarisation evoked from some brainstem areas (FTP, FTC, RMc) could be reversed to depolarisation by the passive diffusion of ions from the recording microelectrode containing 3M-KCl. Brainstem (LC, NRM, FTP, FTL) stimulation generated long lasting (700 ms) hyperpolarisation on 4/4 selectively nocireceptive neurones of lamina I. There was, however, no effect on the activity of 5/5 neurones recorded in laminae I/II which in addition to receiving excitatory cutaneous inputs were inhibited by heat stimuli. Stimulation in LC also produced dorsal root potentials (DRPs) and reduced the amplitude of simultaneously recorded excitatory postsynaptic potentials (EPSPs) generated by the activation of primary afferent fibres in 3 multireceptive neurones. It is concluded that inhibition of nociceptive transmission in the spinal cord from LC and other brainstem areas may involve both pre- and postsynaptic mechanisms.     

Stimulation of locus coeruleus increases arterial pressure in rabbits

目的：研究电刺激和化学刺激兔蓝斑（ＬＣ）对动脉血压（ＡＰ）和肾交感神经传出活动（ＲＳＡ）的影响．方法：电刺激ＬＣ，ＬＣ微量注射ＬＧｌｕ、盐酸吗啡、ＧＡＢＡ、电解毁损ＬＣ，记录ＡＰ和ＲＳＡ．结果：电刺激ＬＣ和ＬＣ注射ＬＧｌｕ均引起ＡＰ升高（分别为１３５±０３ｖｓ１９５±０８ｋＰａ和１３８±０４ｖｓ１７５±０８ｋＰａ）和ＲＳＡ增加．ＬＣ注射吗啡、ＧＡＢＡ对ＡＰ和ＲＳＡ无明显影响．电解毁损ＬＣ后电刺激ＬＣ区、ＬＣ区注射ＬＧｌｕ对ＡＰ和ＲＳＡ无明显影响．结论：兔ＬＣ兴奋引起ＡＰ升高和ＲＳＡ增加，但ＬＣ不是ＡＰ和ＲＳＡ的紧张性中枢．     

Absent chondrodysplasia punctata in a male with an Xp terminal deletion involving the putative region for CDPX1 locus

This is a follow-up report on a male patient with a 46, Y, r(X) karyotype. Although he had no clinico-radiological features of X-linked recessive chondrodysplasia punctata (CDPX1), molecular studies revealed an Xp terminal deletion involving the putative region for the CDPX1 locus (PABX-DXS31). We suspect that the absence of CDPX1 may be attributable to the nature of the disease and the extreme short stature of the patient (mean – 5.6 S.D.). © 1993 Wiley-Liss, Inc.     

Optimal Selection of Sib Pairs from Random Samples for Linkage Analysis of a QTL Using the EDAC Test

Percentages of extremely concordant and extremely discordant sib pairs are calculated that maximize the power to detect a quantitative trait locus (QTL) under a variety of circumstances using the EDAC test. We assume a large fixed number of randomly sampled sib pairs, such as one would hope to find in the large twin registries, and limited resources to genotype a certain number of selected sib pairs. Our aim is to investigate whether optimal selection can be achieved when prior knowledge concerning the QTL gene action, QTL allele frequency, QTL effect size, and background (residual) sib correlation is limited or absent. To this end we calculate the best selection percentages for a large number of models, which differ in QTL gene action allele frequency, background correlation, and QTL effect size. By averaging these percentages over gene action, over allele frequency, over gene action, and over allele frequencies, we arrive at general recommendations concerning selection percentages. The soundness of these recommendations is subsequently in a number of test cases.     

Genotype at a major locus with large effects on apolipoprotein B levels predicts familial combined hyperlipidemia

A sample enriched for familial combined hyperlipidemia (FCHL) was examined for evidence of an association between genotype at an apolipoprotein B (apoB) elevating locus defined by complex segregation analysis and FCHL. Complex segregation analysis detected a locus with a large effect on plasma apoB levels and was used to compute the most probable genotype of family members. None of the 35 normolipidemic adults carried a copy of the allele associated with elevated apoB levels, yet 58% of the 109 adults with FCHL carried 1 (29%) or 2 (28%) copies. Two of 28 (7%) normal children had 1 copy of this allele and none had 2 copies, while 88 of 182 (48%) children with FCHL had 1 (26%) or 2 (22%) copies. Further, 4l of 48 (85%) individuals classified as having hyperapobetalipoproteinemia did not carry a copy of this “elevated apoB” allele. Therefore, the presence of the allele associated with elevation of apoB level is highly predictive of FCHL and this association cannot be explained solely by the presence of elevated apoB levels in FCHL, suggesting that the locus controlling apoB levels may play an etiologic role in FCHL. © 1993 Wiley-Liss, Inc.