Development has the answer: Unraveling psychiatric disorders via thalamocortical organoids.

Dissecting the role of the thalamus in neuropsychiatric disorders requires new models to analyze complex genetic interactions. In this issue of Cell Stem Cell, Shin et al. use patient-derived thalamocortical organoids to investigate 22q11.2 microdeletion impact on thalamic development, revealing significant transcriptional dysregulation linked to psychiatric disorders.

Closed hyperthermic intraperitoneal chemotherapy with CO2 recirculation system compared with the open Coliseum technique in peritoneal malignity treatment.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis can be performed in two ways: first, the standard open abdominal technique (Open HIPEC); or second, the closed technique. In recent years, a new technique has been introduced to perform closed HIPEC; the Peritoneal Recirculation System (PRS-1.0 Combat) with CO2 recirculation technology (PRS Closed HIPEC). The objective of this study is to present our experience with the PRS Closed HIPEC by comparing the intraoperative, postoperative and oncological results with the standard Open HIPEC technique (the Coliseum technique). METHODS: Data on patients undergoing CRS and HIPEC at the Sanchinarro University Hospital, Madrid from October 2012 to June 2021 were collected in a prospective database. The inclusion criteria were patients with primary or recurrent peritoneal metastases in gastrointestinal malignancies or ovarian cancer. The presence of an unresectable peritoneal carcinomatosis, the coexistence of another oncological disease, unresectable and distant metastases were the exclusion criteria. RESULTS: From October 2014 to June 2021, 84 patients underwent CRS and HIPEC at the Sanchinarro University Hospital, Madrid with curative intent. Since the introduction of the PRS Closed HIPEC technique in 2016, 65 patients have been treated. Before the introduction of PRS Closed HIPEC, 19 cases were performed using the Coliseum technique (the Open HIPEC group). The intraoperative results were similar in the two groups. Complete cytoreduction was achieved in all cases in the Open HIPEC group and in 98% in the PRS Closed HIPEC group. The rate of major complications was similar between the groups. Median Overall Survival (OS) resulted better in the Closed HIPEC group (67 months) with respecto to the Open group (43 months) (p < 0,001). Median Disease-Free Survival (DFS) was 15 months in the Open HIPEC group and 40 months in the PRS Closed HIPEC group (p < 0.001). CONCLUSION: The Peritoneal Recirculation System with CO2 recirculation technology (PRS Closed HIPEC) is a reproducible and safe technique and may represent a valid alternative for the administration of HIPEC.

Enhancing tellurite and selenite bioconversions by overexpressing a methyltransferase from Aromatoleum sp. CIB.

Pollution by metalloids, e.g., tellurite and selenite, is of serious environmental concern and, therefore, there is an increasing interest in searching for ecologically friendly solutions for their elimination. Some microorganisms are able to reduce toxic tellurite/selenite into less toxic elemental tellurium (Te) and selenium (Se). Here, we describe the use of the environmentally relevant ß-proteobacterium Aromatoleum sp. CIB as a platform for tellurite elimination. Aromatoleum sp. CIB was shown to tolerate 0.2 and 0.5 mM tellurite at aerobic and anaerobic conditions, respectively. Furthermore, the CIB strain was able to reduce tellurite into elemental Te producing rod-shaped Te nanoparticles (TeNPs) of around 200 nm length. A search in the genome of Aromatoleum sp. CIB revealed the presence of a gene, AzCIB_0135, which encodes a new methyltransferase that methylates tellurite and also selenite. AzCIB_0135 orthologs are widely distributed in bacterial genomes. The overexpression of the AzCIB_0135 gene both in Escherichia coli and Aromatoleum sp. CIB speeds up tellurite and selenite removal, and it enhances the production of rod-shaped TeNPs and spherical Se nanoparticles (SeNPs), respectively. Thus, the overexpression of a methylase becomes a new genetic strategy to optimize bacterial catalysts for tellurite/selenite bioremediation and for the programmed biosynthesis of metallic nanoparticles of biotechnological interest.

International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn.

Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.

Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming.

Neural cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterized by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and astrocytes. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across these two brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis reveals the existence of common nucleus-specific progenitors for neurons and astrocytes. Consistent with their shared molecular signature, regional specificity is maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.

Iodine status and supplementation before, during, and after pregnancy.

Iodine intake is essential for the production of thyroid hormone. Iodine deficiency remains a public health problem in many regions around the world. Iodine deficiency can present as a spectrum of disorders depending on the degree of severity. Pregnant and lactating women are particularly vulnerable to iodine deficiency disorders because of their increased iodine requirements. Severe maternal iodine deficiency has been associated with cretinism or impaired neurodevelopment in children as well as obstetric complications. Universal salt iodization has been shown to prevent these disorders in severely iodine deficient areas. Recently, observational studies have demonstrated an association between mild-to-moderate iodine deficiency and poorer cognitive outcomes in children. In this review, we describe the iodine requirements for pregnant and lactating women, how population iodine status can be assessed, the effects of maternal iodine deficiency and excess, and current data regarding efficacy of iodine supplementation for women who are pregnant or lactating.

Speeding up bioproduction of selenium nanoparticles by using Vibrio natriegens as microbial factory.

Selenium and selenium nanoparticles (SeNPs) are extensively used in biomedicine, electronics and some other industrial applications. The bioproduction of SeNPs is gaining interest as a green method to manufacture these biotechnologically relevant products. Several microorganisms have been used for the production of SeNPs either under aerobic or anaerobic conditions. Vibrio natriegens is a non-pathogenic fast-growing bacterium, easily cultured in different carbon sources and that has recently been engineered for easy genetic manipulation in the laboratory. Here we report that V. natriegens was able to perfectly grow aerobically in the presence of selenite concentrations up to 15 mM with a significant survival still observed at concentrations as high as 100 mM selenite. Electron microscopy and X-ray spectroscopy analyses demonstrate that V. natriegens cells growing aerobically in selenite-containing LB medium at 30 °C produced spherical electron-dense SeNPs whose size ranged from 100-400 nm. Selenite reduction just started at the beginning of the exponential growth phase and the release of SeNPs was observed after cell lysis. Remarkably, V. natriegens produced SeNPs faster than other described microorganisms that were proposed as model bioreactors for SeNPs production. Thus, the fast-growing V. natriegens bacterium becomes a suitable biocatalyst for bioremediation of selenite and for speeding-up the eco-friendly synthesis of SeNPs.

Microcrystalline Tyrosine (MCT®): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria.

Microcrystalline Tyrosine (MCT®) is a widely used proprietary depot excipient in specific immunotherapy for allergy. In the current study we assessed the potential of MCT to serve as an adjuvant in the development of a vaccine against malaria. To this end, we formulated the circumsporozoite protein (CSP) of P. vivax in MCT and compared the induced immune responses to CSP formulated in PBS or Alum. Both MCT and Alum strongly increased immunogenicity of CSP compared to PBS in both C57BL/6 and BALB/c mice. Challenge studies in mice using a chimeric P. bergei expressing CSP of P. vivax demonstrated clinically improved symptoms of malaria with CSP formulated in both MCT and Alum; protection was, however, more pronounced if CSP was formulated in MCT. Hence, MCT may be an attractive biodegradable adjuvant useful for the development of novel prophylactic vaccines.

Biosynthesis of selenium nanoparticles by Azoarcus sp. CIB.

BACKGROUND: Different bacteria have been reported so far that link selenite resistance to the production of metallic selenium nanoparticles (SeNPs). Although SeNPs have many biotechnological applications in diverse areas, the molecular mechanisms involved in their microbial genesis are not fully understood. The Azoarcus genus is a physiologically versatile group of beta-proteobacteria of great environmental relevance. Azoarcus sp. CIB is a facultative anaerobe that combines the ability to degrade under aerobic and/or anaerobic conditions a wide range of aromatic compounds, including some toxic hydrocarbons such as toluene and m-xylene, with an endophytic life style in the root of rice. We unravel here an additional physiological feature of the strain CIB that is related to its resistance to selenium oxyanions and the formation of SeNPs. RESULTS: This work is the first report of a member of the Azoarcus genus that is able to anaerobically grow in the presence of selenite. Electron microscopy preparations and X-ray spectroscopy analyses demonstrate the reduction of selenite to spherical electron-dense SeNPs whose average size was 123 ± 35 nm of diameter. Our data suggest that the main molecular mechanism of selenite resistance resides on an energy-dependent selenite exporter. Azoarcus cells trigger the synthesis of SeNPs when they reach the stationary-phase of growth, and either the exhaustion of electron donor or acceptor, both of which lead to starvation conditions, produce the reduction of selenite to red elemental selenium. Azoarcus becomes a promising biocatalyst, either as whole cells or cellular extracts, for the anaerobic and/or aerobic green synthesis of SeNPs. CONCLUSIONS: Azoarcus turns out to be a new eco-friendly system to reduce selenite and produce spherical SeNPs. Moreover, this is the first report of a rice endophyte able to produce SeNPs. Since Azoarcus is also able to degrade both aerobically and anaerobically toxic aromatic compounds of great environmental concern, it becomes a suitable candidate for a more sustainable agricultural practice and for bioremediation strategies.

Water-in-oil microemulsions versus emulsions as carriers of hydroxytyrosol: an in vitro gastrointestinal lipolysis study using the pHstat technique.

Water-in-oil (W/O) microemulsions and emulsions based on medium chain triglycerides (MCT) were successfully formulated with the addition of emulsifiers and used as encapsulation matrices for hydroxytyrosol (HT), an antioxidant naturally found in extra virgin olive oil. The digestibility of these edible W/O dispersions by recombinant dog gastric lipase (rDGL) and porcine pancreatic lipase (PPL) was then tested at different pH values using a pHstat device. rDGL and PPL displayed a much lower activity on the W/O microemulsion than that on the W/O emulsion and MCT alone. This was explained by the presence of higher amounts of emulsifiers (4.9% w/w lecithin and monoglycerides) in the composition of W/O microemulsions compared to W/O emulsions (1.3% w/w emulsifiers). These surfactants also induced a shift of maximum lipase activity towards lower pH values, which usually reflects the competition between surfactants and lipases for binding at the lipid-water interface. rDGL and PPL were then used consecutively in a two-step digestion model mimicking the conditions found in the human gastrointestinal tract. Direct titration and back-titration of free fatty acids allowed the continuous estimation of lipolysis rates under both gastric and duodenal conditions. Gastric lipolysis of W/O microemulsions was reduced 6 to 9-fold compared to W/O emulsions. This inhibition had a major impact on the overall lipolysis, although duodenal lipolysis was less affected by the dispersion type. The presence of HT had also some minor effects on lipolysis rates.

Biochemical characterization of Yarrowia lipolytica LIP8, a secreted lipase with a cleavable C-terminal region.

Yarrowia lipolytica is a lipolytic yeast possessing 16 paralog genes coding for lipases. Little information on these lipases has been obtained and only the major secreted lipase, namely YLLIP2, had been biochemically and structurally characterized. Another secreted lipase, YLLIP8, was isolated from Y. lipolytica culture medium and compared with the recombinant enzyme produced in Pichia pastoris. N-terminal sequencing showed that YLLIP8 is produced in its active form after the cleavage of a signal peptide. Mass spectrometry analysis revealed that YLLIP8 recovered from culture medium lacks a C-terminal part of 33 amino acids which are present in the coding sequence. A 3D model of YLLIP8 built from the X-ray structure of the homologous YLLIP2 lipase shows that these truncated amino acids in YLLIP8 belong to an additional C-terminal region predicted to be mainly helical. Western blot analysis shows that YLLIP8 C-tail is rapidly cleaved upon enzyme secretion since both cell-bound and culture supernatant lipases lack this extension. Mature recombinant YLLIP8 displays a true lipase activity on short-, medium- and long-chain triacylglycerols (TAG), with an optimum activity at alkaline pH on medium chain TAG. It has no apparent regioselectivity in TAG hydrolysis, thus generating glycerol and FFAs as final lipolysis products. YLLIP8 properties are distinct from those of the 1,3-regioselective YLLIP2, acting optimally at acidic pH. These lipases are tailored for complementary roles in fatty acid uptake by Y. lipolytica.

FLRT3 is a Robo1-interacting protein that determines Netrin-1 attraction in developing axons.

BACKGROUND: Guidance molecules are normally presented to cells in an overlapping fashion; however, little is known about how their signals are integrated to control the formation of neural circuits. In the thalamocortical system, the topographical sorting of distinct axonal subpopulations relies on the emergent cooperation between Slit1 and Netrin-1 guidance cues presented by intermediate cellular targets. However, the mechanism by which both cues interact to drive distinct axonal responses remains unknown. RESULTS: Here, we show that the attractive response to the guidance cue Netrin-1 is controlled by Slit/Robo1 signaling and by FLRT3, a novel coreceptor for Robo1. While thalamic axons lacking FLRT3 are insensitive to Netrin-1, thalamic axons containing FLRT3 can modulate their Netrin-1 responsiveness in a context-dependent manner. In the presence of Slit1, both Robo1 and FLRT3 receptors are required to induce Netrin-1 attraction by the upregulation of surface DCC through the activation of protein kinase A. Finally, the absence of FLRT3 produces defects in axon guidance in vivo. CONCLUSIONS: These results highlight a novel mechanism by which interactions between limited numbers of axon guidance cues can multiply the responses in developing axons, as required for proper axonal tract formation in the mammalian brain.

Spontaneous activity regulates Robo1 transcription to mediate a switch in thalamocortical axon growth.

Developing axons must control their growth rate to follow the appropriate pathways and establish specific connections. However, the regulatory mechanisms involved remain elusive. By combining live imaging with transplantation studies in mice, we found that spontaneous calcium activity in the thalamocortical system and the growth rate of thalamocortical axons were developmentally and intrinsically regulated. Indeed, the spontaneous activity of thalamic neurons governed axon growth and extension through the cortex in vivo. This activity-dependent modulation of growth was mediated by transcriptional regulation of Robo1 through an NF-κB binding site. Disruption of either the Robo1 or Slit1 genes accelerated the progression of thalamocortical axons in vivo, and interfering with Robo1 signaling restored normal axon growth in electrically silent neurons. Thus, modifications to spontaneous calcium activity encode a switch in the axon outgrowth program that allows the establishment of specific neuronal connections through the transcriptional regulation of Slit1 and Robo1 signaling.

Emergent growth cone responses to combinations of Slit1 and Netrin 1 in thalamocortical axon topography.

How guidance cues are integrated during the formation of complex axonal tracts remains largely unknown. Thalamocortical axons (TCAs), which convey sensory and motor information to the neocortex, have a rostrocaudal topographic organization initially established within the ventral telencephalon [1-3]. Here, we show that this topography is set in a small hub, the corridor, which contains matching rostrocaudal gradients of Slit1 and Netrin 1. Using in vitro and in vivo experiments, we show that Slit1 is a rostral repellent that positions intermediate axons. For rostral axons, although Slit1 is also repulsive and Netrin 1 has no chemotactic activity, the two factors combined generate attraction. These results show that Slit1 has a dual context-dependent role in TCA pathfinding and furthermore reveal that a combination of cues produces an emergent activity that neither of them has alone. Our study thus provides a novel framework to explain how a limited set of guidance cues can generate a vast diversity of axonal responses necessary for proper wiring of the nervous system.

Conservation laryngeal surgery versus total laryngectomy for radiation failure in laryngeal cancer.

BACKGROUND: Total laryngectomy is the standard of care for surgical salvage of radiation failure in laryngeal cancer. However, the role of conservation laryngeal surgery in this setting remains unclear. The objective was to compare the efficacy of conservation versus total laryngectomy for salvage of radiation failure in patients who initially presented with T1 or T2 squamous cancer of the larynx. METHODS: A 21-year retrospective analysis of patients who received surgery at a single comprehensive cancer center after definitive radiation therapy is reported. At recurrence, the patients were reevaluated and then underwent a total laryngectomy or, if possible, a conservation laryngeal procedure. The charts of 105 patients who failed radiation treatment for primary laryngeal cancer and who subsequently underwent surgical salvage were reviewed for this study. Eighty-nine were male (84.8%). The mean age was 60.3 years. The median follow-up time after surgery was 69.4 months. Most patients with recurrence after radiotherapy required total laryngectomy (69.5%; 73/105). Conservation laryngeal surgery was performed for 32 patients (31.5%). Concomitant neck dissections were performed on 45 patients (45.5%). RESULTS: In 14 patients, local or regional recurrence developed after salvage surgery: 9 patients after total laryngectomy (12.3%; 9/73), and 5 patients (15.6%; 5/32) after conservation laryngeal surgery. This difference was not statistically significant, nor was there a difference in disease-free interval for the two procedures (p = .634, by log-rank test). Distant metastasis developed in 13 patients. Most developed in the setting of local and/or regional recurrence, but distant metastasis occurred as the only site of failure in 6 of the patients who had undergone total laryngectomy but in 1 of the conservation surgery patients treated for a supraglottic laryngeal cancer. The overall mortality for patients who underwent total laryngectomy was also higher: 73.74% (54/73) versus 59.4% (19/32) for patients who underwent a conservation approach (p = .011 by log-rank test). CONCLUSIONS: Although conservation laryngeal surgery was possible in a few patients with local failure after radiotherapy, conservation laryngeal surgery is an oncologically sound alternative to total laryngectomy for these patients.

Donación autóloga en una gestante con anticuerpos antieritrocitarios anti-U y anti-He (Henshaw) / Autologous tranfussion in a pregnant with anti-U and anti-He (Henshaw)

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Olfactory neuroblastoma: the 22-year experience at one comprehensive cancer center.

BACKGROUND: Olfactory neuroblastoma (ONB) is a rare tumor arising from the olfactory neuroepithelium. There is no universally accepted staging system, and treatment approaches lack uniformity. We present one institution's experience with this tumor and the results of therapy. METHODS: Thirty patients treated for ONB at The University of Texas M. D. Anderson Cancer Center between 1979 and 2002 were retrospectively reviewed. The diagnosis of ONB was histologically confirmed for each patient. RESULTS: The mean follow-up was 7.32 years. In 77% of cases, patients received treatment with surgery followed by postoperative radiation therapy. Sixteen percent received chemotherapy as part of their initial treatment. Overall 5-year and 10-year survival rates were 89% and 81%, respectively. Nine patients whose disease was initially stage C had a recurrence. The mean time for recurrence was 4.67 years. CONCLUSIONS: The M. D. Anderson Cancer Center approach to ONB is complete surgical resection, usually involving a craniofacial approach, with postoperative radiation therapy. This approach seems to be curative in early-stage disease. Late recurrence warrants long-term follow-up.

Parathyroid carcinoma: a 22-year experience.

PURPOSE: Because parathyroid carcinoma is rare, clear consensus is not available regarding the optimal management of patients with this condition. Treatment strategies generally derive from clinical and anecdotal experiences. We report our experience with this entity. METHODS: We included all patients with parathyroid carcinoma seen at The University of Texas M. D. Anderson Cancer Center since January 1, 1980. The medical records and pathology specimens were reviewed and verified in all cases. RESULTS: Since 1980, 27 patients (16 men and 11 women) registered at M. D. Anderson Cancer Center with parathyroid carcinoma and a minimum follow-up of 2 years. The age at initial diagnosis (mean +/- SD) was 46.7 +/- 15.3 years. All patients were seen with hypercalcemia (mean calcium, 13.4 +/- 1.5 mg/dL). Eighteen patients had locally invasive disease, eight had localized disease, and one had distant metastasis. Parathyroid cancer was treated with complete surgical excision with curative intent in 18 patients. In the other nine patients, who had clinical and/or radiographic evidence of soft tissue extension, the tumor was treated by comprehensive "en bloc" soft tissue resection. Of six patients who received adjuvant radiotherapy after initial surgery, only one had a local relapse. In contrast, of 20 patients who did not receive adjuvant radiotherapy, 10 had a local relapse, excluding the one patient who had distant metastases. The 5-year survival was 85%, and the 10-year survival was 77%. Five patients died of parathyroid carcinoma; all deaths were hypercalcemia related. CONCLUSIONS: Parathyroid carcinoma can be an indolent disease with morbidity and mortality related to hypercalcemia. Adjuvant radiotherapy may improve local control and limit the occurrence of local relapse. A comprehensive multidisciplinary approach with surgery, radiation therapy, and medical treatment for hypercalcemia is needed to optimize patient outcome.