A prospective,iterative, adaptive trial of carfilzomib‐based desensitization

Proteasome inhibitor–based strategies hold promise in transplant but have yielded varying results. Carfilzomib, a second‐generation proteasome inhibitor, may possess advantages over bortezomib, the first‐generation proteasome inhibitors. The purpose of this study was to evaluate the safety, toxicity, and preliminary efficacy of carfilzomib in highly HLA‐sensitized kidney transplant candidates. Renal transplant candidates received escalating doses of carfilzomib followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Thirteen participants received carfilzomib, which was well tolerated with most adverse events classified as low grade. The safety profile was similar to bortezomib desensitization; however, neurotoxicity was not observed with carfilzomib. Toxicity resulted in permanent dose reduction in 1 participant but caused no withdrawals or deaths. HLA antibodies were substantially reduced with carfilzomib alone, and median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B, P = .938). After depletion, rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141. Bone marrow studies revealed that approximately 69.2% of plasma cells were depleted after carfilzomib monotherapy. Carfilzomib monotherapy–based desensitization provides an acceptable safety and toxicity profile while leading to significant bone marrow plasma cell depletion and anti‐HLA antibody reduction.     

Tailored use of belatacept in adolescent kidney transplantation

Adolescent transplant recipients are at risk for nonadherence, development of de novo donor‐specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor‐based regimens in adults; however, its use in children is scant. Three adolescents were initiated on belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid‐free belatacept and sirolimus for two patients. One patient was initially maintained steroid‐free on belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy‐proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m² at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid‐responsive acute cellular rejection. Belatacept‐based regimens can be tailored for adolescent recipients with good short‐term clinical outcomes.     

Trained immunity in organ transplantation

Consistent induction of donor‐specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen‐presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long‐term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro‐inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection.     

Characteristics of Diprophylline-Induced Bidirectional Modulation on Rat Jejunal Contractility

In this study, we propose that diprophylline exerts bidirectional modulation (BM) on the isolated rat jejunal segment depending on its contractile state. The results supported the hypothesis. Diprophylline (20 µM) exerted stimulatory effects on the contractility of jejunal segment in six low contractile states while inhibitory effects in six high contractile states, showing the characteristics of BM. Diprophylline-induced stimulatory effect was significantly blocked by atropine, indicating the correlation with cholinergic activation. Diprophylline-induced inhibitory effect was partially blocked by phentolamine, propranolol, and L-N-Nitro-Arginine respectively, indicating their correlation with sympathetic activation and nitric oxide-mediated relaxing mechanisms. Diprophylline-induced BM was abolished by tetrodotoxin or in a Ca²⁺ free condition or pretreated with tyrosine kinase inhibitor imatinib, suggesting that diprophylline-induced BM is Ca²⁺ dependent, and that it requires the presence of enteric nervous system as well as pacemaker activity of interstitial cells of Cajal. Diprophylline significantly increased the reduced MLCK expression and myosin extent in constipation-prominent rats and significantly decreased the increased MLCK expression and myosin extent in diarrhea-prominent rats, suggesting that the change of MLCK expression may also be involved in diprophylline-induced BM on rat jejunal contractility. In summary, diprophylline-exerted BM depends on the contractile states of the jejunal segments, requires the presence of Ca²⁺, enteric nervous system, pacemaker activity of interstitial cells of Cajal, and MLCK-correlated myosin phosphorylation. The results suggest the potential implication of diprophylline in relieving alternative hypo/hyper intestinal motility.     

Gut microbiome interventions in human health and diseases

Ongoing studies have determined that the gut microbiota is a major factor influencing both health and disease. Host genetic factors and environmental factors contribute to differences in gut microbiota composition and function. Intestinal dysbiosis is a cause or a contributory cause for diseases in multiple body systems, ranging from the digestive system to the immune, cardiovascular, respiratory, and even nervous system. Investigation of pathogenesis has identified specific species or strains, bacterial genes, and metabolites that play roles in certain diseases and represent potential drug targets. As research progresses, gut microbiome–based diagnosis and therapy are proposed and applied, which might lead to considerable progress in precision medicine. We further discuss the limitations of current studies and potential solutions.     

Potential of curcumin and resveratrol as biochemical and biophysical modulators during lung cancer in rats

The present study explored chemopreventive aspects of curcumin and resveratrol in the experimental model of lung carcinogenesis in rats. The main aim was to establish efficacy of combined phytochemicals treatment over individual treatments in rat cancer model. The study was performed in terms of both biophysical and biochemical parameters. The rats were segregated into five groups, which included normal control, benzo[a]pyrene (BP) treated, BP?+?curcumin treated, BP?+?resveratrol treated, and BP?+?curcumin?+?resveratrol treated groups. The results confirmed significant changes in the biochemical indices of the BP treated rats. Further, radiorespirometric studies showed significant rise in the ¹⁴C-glucose turnover and uptakes in BP treated rats. Also, a significant increase in the cell proliferation was noticed indirectly by recording uptakes of ³H-thymidine in the lung slices of BP treated rats. On the other hand, supplementation with curcumin and resveratrol in combination to BP treated rats significantly modulated both biophysical and biochemical indices. The histopathological studies also supported the efficacy of combined treatment of phytochemicals during lung carcinogenesis. The present study concluded that the combination of curcumin and resveratrol efficiently modulated lung carcinogenesis in rats.     

Cortical control of adaptation and sensory relay mode in the thalamus

A major synaptic input to the thalamus originates from neurons in cortical layer 6 (L6); however, the function of this cortico–thalamic pathway during sensory processing is not well understood. In the mouse whisker system, we found that optogenetic stimulation of L6 in vivo results in a mixture of hyperpolarization and depolarization in the thalamic target neurons. The hyperpolarization was transient, and for longer L6 activation (>200 ms), thalamic neurons reached a depolarized resting membrane potential which affected key features of thalamic sensory processing. Most importantly, L6 stimulation reduced the adaptation of thalamic responses to repetitive whisker stimulation, thereby allowing thalamic neurons to relay higher frequencies of sensory input. Furthermore, L6 controlled the thalamic response mode by shifting thalamo–cortical transmission from bursting to single spiking. Analysis of intracellular sensory responses suggests that L6 impacts these thalamic properties by controlling the resting membrane potential and the availability of the transient calcium current I_T, a hallmark of thalamic excitability. In summary, L6 input to the thalamus can shape both the overall gain and the temporal dynamics of sensory responses that reach the cortex.Sensory signals en route to the cortex undergo profound signal transformations in the thalamus. One important thalamic transformation is sensory adaptation. Adaptation is a common characteristic of sensory systems in which neural output adjusts to the statistics and dynamics of past stimuli, thereby better encoding small stimulus changes across a wide range of scales despite the limited range of possible neural outputs (1–3). Thalamic sensory adaptation is characterized by a steep decrease in action potential (AP) activity during sustained sensory stimulation (4–7), decreasing the efficacy at which subsequent sensory stimuli are transmitted to the cortex.The widely reported duality of thalamic response mode is another key property of thalamic information processing which further affects how sensory input reaches the cortex. In burst mode, sensory inputs are relayed as short, rapid clusters of APs; in contrast, in tonic mode the same inputs are translated into single APs. Both tonic and burst modes have been described during anesthesia/sleep and wakefulness/behavior, with a pronounced shift toward the tonic mode during alertness (8–12).Although the exact information content of thalamic bursts is not yet clear, it has been suggested that bursting may signal novel stimuli to the cortex, whereas the tonic mode enables linear encoding of fine stimulus details, e.g., when an object is examined (13, 14). One issue hampering the interpretation of burst/tonic responses is that currently it is unknown if the cortex itself is involved in the rapid changes in firing modes seen in the awake and anesthetized animal (15, 16) and which mechanisms initiate these shifts in vivo.On the biophysical level, the response mode depends on the resting membrane potential (RMP), which controls the availability of the transient low-threshold calcium current (I_T) (17). Depolarization decreases the size of the I_T-mediated low-threshold calcium spike (LTS), and fewer burst spikes are fired (18). Similarly, RMP influences adaptation in that depolarization reduces the voltage distance to the AP threshold, thereby increasing the probability that smaller, depressed inputs will trigger APs (6). Thus, the dynamics of the RMP may govern several key properties of signal transformation in the thalamus, thereby providing a common mechanism for controlling thalamic adaptation and response mode.Although subcortical inputs have been shown to influence thalamic firing modes (7, 9), we investigated the impact of cortical activity on thalamic sensory processing. Cortico–thalamic projections from cortical layer 6 (L6) are a likely candidate for regulating thalamic sensory processing with high spatial and temporal precision, because these projections provide a major input to the thalamus and, as shown by McCormick et al. (19), depolarize and modulate firing of thalamic cells in vitro.However, because of the inability to study sensory signals in brain slices, the role of L6 on thalamic input/output properties during sensory processing is not clear. Here, in the ventro posteromedial nucleus (VPM) of the mouse whisker thalamus, we investigate how L6 impacts the transmission of whisker inputs to the cortex. Recent advances in cell-type–specific approaches to dissect specific circuits in vivo (20–22) allowed us to activate the L6–thalamic pathway specifically and determine its impact on thalamic sensory processing.We found that cortical L6 can change key properties of thalamic sensory processing by controlling the interaction of intrinsic membrane properties and sensory inputs. This mechanism enables the cortex to control the frequency-dependent adaptation and the gain of its own input.