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Background: The technique of « en bloc» liver and small bowel transplantation (L‐BT) spares a biliary anastomosis, but does not protect against biliary complications. We analyze biliary and duodenal complications (BDC) in our pediatric series. Methods: Between 1994 and 2020, 54 L‐BT were performed in 53 children. The procurement technique included in situ vascular dissection and pancreatic reduction to the head until 2009 (group A). Thereafter, the whole pancreas was recovered (group B). Results: Nine BDCs occurred in 8/53 (15%) patients (7 in group A and 1 in group B): leak of the donor's duodenal stump (2), stenosis of the extra‐pancreatic bile duct (5), and intra‐pancreatic bile duct stenosis (2). Median delay for diagnosis of stricture was 8 months (4–168). Interventional radiology was successful in one child only, the others required reoperations. Two patients died, of biliary cirrhosis or cholangitis, 15‐month and 12‐year post‐L‐BT. One was listed and liver re‐transplanted 13 years post‐L‐BT. At last follow‐up, two patients only had normal liver tests and ultrasound. Conclusion: BDC after L‐BT can cause severe morbidities. Pancreatic reduction might increase this risk. Early surgical complications or chronic pancreatic rejection might be co‐factors. Early diagnosis and treatment are key to the long‐term prognosis. [ABSTRACT FROM AUTHOR]

Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long‐term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune‐dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm‐selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction. Synopsis: Anticancer drugs that trigger immunogenic cell death (ICD) are particularly efficient because they mobilize the host immune system against malignant cells expressing tumor‐associated antigens. Dactinomycin is identified as an ICD inducer and showed to stimulate anticancer immune responses in vivo. An algorithm designed to discover cancer cell‐killing drugs with immunostimulatory properties led to the identification of dactinomycin (DACT, also known as actinomycin D), as an ICD inducer.DACT induces all hallmarks ICD including phosphorylation of eukaryotic initiation factor 2a (eIF2a) in the context of a partial endoplasmic reticulum stress response, as well as cell surface exposure of calreticulin.DACT stimulated anticancer immune responses in vivo with an improvement of the ratio of cytotoxic T lymphocytes over regulatory T cells in tumor‐infiltrating lymphocytes, while sensitizing tumors to subsequent immunotherapy with a PD‐1‐blocking antibody.DACT is a known transcriptional inhibitor, and a range of distinct ICD inducers were found to potently inhibit transcription and translation, as documented for anthracyclines, crizotinib, lurbinectedin and oxaliplatin.Artificial intelligence applied to a library of 50,000 drugs corroborated that transcription and translation inhibitors have a higher probability to induce ICD than other classes of antineoplastics. [ABSTRACT FROM AUTHOR]

Abstract: Preclinical evidence depicts the capacity of redaporfin (Redp) to act as potent photosensitizer, causing direct antineoplastic effects as well as indirect immune‐dependent destruction of malignant lesions. Here, we investigated the mechanisms through which photodynamic therapy (PDT) with redaporfin kills cancer cells. Subcellular localization and fractionation studies based on the physicochemical properties of redaporfin revealed its selective tropism for the endoplasmic reticulum (ER) and the Golgi apparatus (GA). When activated, redaporfin caused rapid reactive oxygen species‐dependent perturbation of ER/GA compartments, coupled to ER stress and an inhibition of the GA‐dependent secretory pathway. This led to a general inhibition of protein secretion by PDT‐treated cancer cells. The ER/GA play a role upstream of mitochondria in the lethal signaling pathway triggered by redaporfin‐based PDT. Pharmacological perturbation of GA function or homeostasis reduces mitochondrial permeabilization. In contrast, removal of the pro‐apoptotic multidomain proteins BAX and BAK or pretreatment with protease inhibitors reduced cell killing, yet left the GA perturbation unaffected. Altogether, these results point to the capacity of redaporfin to kill tumor cells via destroying ER/GA function. [ABSTRACT FROM AUTHOR]

Objective To evaluate clinical use of a tunica vaginalis flap as the dorsal component of a two-stage urethroplasty in boys with cripple hypospadias. Patients and Methods We performed the first stage of a Bracka two-stage urethroplasty, using a tunica vaginalis flap as the dorsal component in six boys with cripple hypospadias. We analysed their clinical characteristics and the results of this technique. Results The mean (range) age of the boys was 57 (34-120) months. The mean (range) number of previous procedures the boys had undergone was 4 (3-5). At the 6-month follow-up, all the boys presented significant fibrosis of the dorsal graft rendering it unusable for tubularisation. Conclusions Exposure to the external environment seems to induce retraction and fibrosis of the tunica vaginalis. We believe one should be very cautious about using tunica vaginalis as the dorsal component of a two-stage urethroplasty, as significant fibrosis might well render the flap unusable. [ABSTRACT FROM AUTHOR]

As a result of advances in medical treatment, almost 80% of children who are diagnosed with cancer survive long-term. The adverse consequences of cancer treatments include impaired puberty and fertility. In prepubertal girls, the only therapeutic option is the cryopreservation of an ovary. To date, a dozen births have been reported after reimplantation of cryopreserved mature ovaries. To analyze ovarian function after immature grafts, we performed ovarian grafting in a ewe model. Fresh or cryopreserved ovaries from immature ewes were autografted in prepubertal or adult ewes. Cyclic hormonal activity was recovered 3 mo after grafting. Histological analysis demonstrated the presence of all follicle populations and corpora lutea not affected by cryopreservation. After 3 reproductive seasons, births had been observed in all groups, and the follicle-stimulating hormone status was under the limit, which indicated an exhausted ovary. As an indicator of potential imprinting default, the methylation status of the Igf2r gene was analyzed and did not show significant alteration compared with that of nonmanipulated animals. Taken together, these results demonstrate that immature ovarian grafting is able to restore spontaneous puberty and fertility and could guide the reimplantation of immature cortex in women. [ABSTRACT FROM AUTHOR]

Chronic intestinal pseudo-obstruction (CIPO) is a severe disease of the digestive tract motility. In pediatric population, CIPO remains of unknown origin for most patients. Chronic intestinal pseudo-obstruction is also a common feature in the course of mitochondrial oxidative phosphorylation disorders related for some patients to mutations in TYMP, POLG1, mtDNA tRNA or tRNA genes. We hypothesized that CIPOs could be the presenting symptom of respiratory chain enzyme deficiency and thus we investigated oxidative phosphorylation in small bowel and/or colon smooth muscle of primary CIPO children. We studied eight children with CIPO and 12 pediatric controls. We collected clinical, radiological and pathological data and measured respiratory chain enzymatic activity in isolated smooth muscle of the small bowel and/or the colon. We also sequenced TYMP, POLG, mtDNA tRNA and tRNA genes. Neither pathological nor radiological data were in favor of a mitochondrial dysfunction. No respiratory chain enzyme deficiency was detected in CIPO children. In myogenic CIPO, respiratory enzymes and citrate synthase activities were increased in small bowel and/or colon whereas no abnormality was noted in neurogenic and unclassified CIPO. Levels of enzyme activities were higher in control small bowel than in control colon muscle. Sequencing of TYMP, POLG, mtDNA tRNA and tRNA genes and POLG gene did not reveal mutation for any of the patients. The normal enzymatic activities as the lack of radiological and genetic abnormalities indicate that, at variance with adult patients, oxidative phosphorylation deficiency is not a common cause of childhood CIPO. [ABSTRACT FROM AUTHOR]

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health‐promoting and longevity‐extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4‐dimethoxychalcone (3,4‐DC), among a library of polyphenols. When added to several different human cell lines, 3,4‐DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well‐characterized CRMs, 3,4‐DC, however, required transcription factor EB (TFEB)‐ and E3 (TFE3)‐dependent gene transcription and mRNA translation to trigger autophagy. 3,4‐DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4‐DC induced autophagy in vitro and in mouse organs, mediated autophagy‐dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4‐DC is a novel CRM with a previously unrecognized mode of action. Synopsis: From a library of polyphenols and polyamines, the 3,4‐dimethoxychalcone (3,4‐DC) was screened and identified as a caloric restriction mimetic (CRM) that induces autophagy through TFEB and TFE3 and results in cardioprotection and improved efficacy of anticancer chemotherapy in mice. 3,4‐DC induces all hallmarks of caloric restriction mimicry, i.e. the combination of autophagy, reduced protein acetylation and absence of toxicity.3,4‐DC induces autophagy in a TFEB‐ and TFE3‐regulated, transcription and translation‐dependent manner.3,4‐DC causes cardioprotection and enhances anticancer effects of chemotherapy in an autophagy‐dependent fashion in vivo in mice. [ABSTRACT FROM AUTHOR]