Immunogenic hydrogel toolkit disturbing residual tumor “seeds” and pre-metastatic “soil” for inhibition of postoperative tumor recurrence and metastasis

Tumor recurrence and metastasis is the leading cause of mortality for postoperative breast cancer patients. However, chemotherapy intervention after surgery is often unsatisfactory, because residual microtumors are difficult to target and require frequent administration. Here, an all-in-one and once-for-all drug depot based on in situ-formed hydrogel was applied to fit the irregular surgical trauma, and enable direct contact with residual tumors and sustained drug release. Our immunological analysis after resection of orthotopic breast tumor revealed that postsurgical activation of CXCR4–CXCL12 signal exacerbated the immunosuppression and correlated with adaptive upregulation of PD-L1 in recurrent tumors. Thus, a multifunctional hydrogel toolkit was developed integrating strategies of CXCR4 inhibition, immunogenicity activation and PD-L1 blockade. Our results showed that the hydrogel toolkit not only exerted local effect on inhibiting residual tumor cell “seeds” but also resulted in abscopal effect on disturbing pre-metastatic “soil”. Furthermore, vaccine-like effect and durable antitumor memory were generated, which resisted a secondary tumor rechallenge in 100% cured mice. Strikingly, one single dose of such modality was able to eradicate recurrent tumors, completely prevent pulmonary metastasis and minimize off-target toxicity, thus providing an effective option for postoperative intervention.KEY WORDS: Hydrogel, Postoperative treatment, Tumor recurrence, Pre-metastatic niche, CXCR4 inhibition, Immunotherapy, Local therapy, Immunogenic cell death     

Cholecystokinin-Mediated Neuromodulation of Anxiety and Schizophrenia: A “Dimmer-Switch” Hypothesis

Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK₁ and CCK₂, expressed at low and high levels in the brain, respectively. Historically, CCK₂ receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK₁ receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK₂ receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.     

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between “seed and soil”

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of “seed and soil” suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.KEY WORDS: Tumor metastasis, Drug delivery systems, Nanomedicine, Metastatic cascade, Seed and soil, Tumor microenvironment, Circulating tumor cells, Premetastatic niche     

Effects of “paralytic shellfish poison” on frog nerve and muscle

A purified extract of toxic lamellibranchs, Saxidomus giganteus (Deshayes), containing “paralytic shellfish poison,” has been tested for its effects on conduction and contraction in frog nerve and muscle. The poison was very toxic and concentrations within the range 0.025 to 0.1 μg/ml. paralysed isolated muscle preparations, with abolition of the muscle action potential. The poison did not readily penetrate the perineurium, but in desheathed sciatic nerves the conduction of nerve impulses was rapidly blocked by concentrations of 0.05 to 0.1 μg/ml. There was no evidence that the poison had any specific curarizing action at the neuromuscular junction, and the paralysis was not accompanied by any appreciable depolarization of the muscle membrane.     

The effect of antidepressants and “tranquillizers” on the response of mice to ethanol

1. The techniques and apparatus used for investigation of the interaction of various psychotropic drugs with ethanol in mice are described. The parameters measured were (a) length of loss of righting reflexes; (b) continuous coma; (c) subjects remaining in coma 12 hr after dosing; (d) changes in toxicity.2. The following drugs were tested: amitriptyline, trimipramine, imipramine, nortriptyline, desipramine, thioridazine, phenelzine, methylphenidate, chlorpromazine, trifluoperazine, phenobarbitone, and diazepam. The total number of mice used was 3,140.3. Imipramine caused no significant changes in the effects of ethanol. Methylphenidate and desipramine protected the mice against ethanol induced coma. All other drugs induced statistically significant potentiation of the depressant and toxic effects of ethanol in mice.4. Late (delayed) deaths after a tricyclic antidepressant have been noted in animals and man.5. It is suggested that the potentiation of alcohol by some psychotropic drugs may add to the hazards of drug overdosage and contribute to traffic accidents. Hence it is necessary to test all psychotropic drugs for interaction with alcohol.     

Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators: insights into different protein behaviors with “short” and “long” inverse agonists

A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the “short” inverse agonist 6. With the increase in the size of the 6-position substituents, the “short” inverse agonist 6 first reversed its function to agonists and then to “long” inverse agonists. The cocrystal structures of RORγt complexed with the representative “short” inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the “long” inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of “short” inverse agonist 6 and “long” inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that “short” or “long” inverse agonists led to different behaviors of helixes H11, H11’, and H12 of RORγt. The “short” inverse agonist 6 destabilizes H11’ and dislocates H12, while the “long” inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.     

Release of “neurokinin” on nervous and electrical stimulation of a frog stomach muscle preparation

Activation of a frog stomach muscle preparation by electrical stimulation of a vagus nerve or by direct stimulation released two polypeptides. One was destroyed by trypsin or chymotrypsin in about 10 min; the activity of the other was enhanced by trypsin for about 10 min, but was destroyed by chymotrypsin. Similar stimulation of dog stomach muscle did not release these polypeptides. Correspondingly, the transmission from vagus nerve to stomach muscle in the frog was resistant to atropine, but was blocked by atropine in the dog.     

Size,shape, charge and “stealthy” surface: Carrier properties affect the drug circulation time in vivo

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time. For most drugs, sufficient in vivo circulation time is the basis of high bioavailability. Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system, to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect. The physical and chemical properties of drug carriers, such as size, shape, surface charge and surface modification, would affect their in vivo circulation time, metabolic behavior and biodistribution. The final circulation time of carriers is determined by the balance between macrophage recognitions, blood vessel penetration and urine excretion. Therefore, when designing the drug delivery system, we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually. This article mainly reviews the effect of carrier size, size, surface charge and surface properties on its circulation time in vivo, and discusses the mechanism of these properties affecting circulation time. This review has reference significance for the research of long-circulation drug delivery system.     

Sex specific effects of “junk-food” diet on calcium permeable AMPA receptors and silent synapses in the nucleus accumbens core

CP-AMPARs in the nucleus accumbens (NAc) mediate cue-triggered motivation for food and cocaine. In addition, increases in NAc CP-AMPAR expression and function can be induced by cocaine or sugary, fatty junk-foods. However, the precise nature of these alterations and the degree to which they rely on the same underlying mechanisms is not well understood. This has important implications for understanding adaptive vs. maladaptive plasticity that drives food- and drug-seeking behaviors. Furthermore, effects of junk-foods on glutamatergic plasticity in females are unknown. Here, we use a combination of protein biochemistry and whole-cell patch clamping to determine effects of diet manipulation on glutamatergic plasticity within the NAc of males and females. We found that junk-food consumption increases silent synapses and subsequently increases CP-AMPAR levels in males in the NAc of male rats. In addition, a brief period of junk-food deprivation is needed for the synaptic insertion of CP-AMPARs and the maturation of silent synapses in males. In contrast, junk-food did not induce AMPAR plasticity in females but may instead alter NMDAR-mediated transmission. Thus, these studies reveal sex differences in the effects of junk-food on NAc synaptic plasticity. In addition, they provide novel insights into how essential food rewards alter NAc function.Subject terms: Reward, Obesity, Motivation, Neurotransmitters     

Heroin smoking by “chasing the dragon” in young opiate users in Ireland: stability and associations with use to “come down” off “Ecstasy”

We explored the frequency of commencing opiate use by “chasing the dragon” to “come down” off Ecstasy and the stability of heroin smoking in young opiate takers by assessing 102 subjects in Dublin using a semistructured interview. Ninety-two subjects had used Ecstasy. Of these, 68 reported “chasing” to “come down” off Ecstasy at some point in their history and were found to have used Ecstasy more frequently and in larger amounts. Thirty-six reported that their first experience of using opiates was to “come down” off Ecstasy, 28 citing this as their main reason for commencement.

Eighty-six of the 102 commenced opiates by “chasing” heroin, 61 of whom progressed to injecting after a mean of 2.9 years. This was associated with starting illicit drug use earlier, starting heroin earlier, and a history of using Ecstasy. Implications for service planners in developing responses to illicit drug use among adolescents are discussed.