A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

BACKGROUND: The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection. METHODS: We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors. FINDINGS: We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor. CONCLUSIONS: Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors. FUNDING: Funded by Fate Therapeutics and NIH (R01CA238039).

Analysis of immunologic comorbidities in ulcerative colitis patients: a tool to prevent exacerbations in ulcerative colitis cases.

There have been previous studies, especially in Western countries and even in some areas in Asia, about extra-intestinal manifestations (EIMs) and its link with the outcome of inflammatory bowel disease (IBD), which includes Crohn's disease (CD), and ulcerative colitis (UC). This link is crucial when discussing a patient's prognosis and important when dealing with UC management. The aim of this study was to clarify the most common comorbidities associated with UC, emphasizing immunologic comorbidities in Japan. This study was a retrospective analysis performed at Nagoya University Hospital. The data collection started in March, 2019, and continued for two years. We retrieved the medical records of 105 patients with UC diagnosis, from which the data of 176 EIMs were extracted and analyzed. Results showed that EIMs with UC in the active phase accounted for 43.7% of total EIMs. Twenty-six patients with immune-mediated inflammatory disease frequently had an active phase (odds ratio [OR] 3.84, 99% CI, 1.44-10.27). Comorbidities showing an active manifestation of symptoms and UC in the active phase were significantly correlated in patients with immunological comorbidities, such as peripheral arthritis (r = 0.97, p < 0.01) and rheumatoid arthritis (RA) (r = 0.99, p < 0.01), as well as in patients with primary sclerosis cholangitis (PSC) (r = 0.98, p < 0.01). In conclusion, this analysis suggests the importance of having full comprehension of how immunological comorbidities affect the natural development of UC, which is of vital importance to prevent further UC complications and properly adjust the management of the disease.

Immunoproliferative Small Intestinal Disease Diagnosed by Double-balloon Endoscopy with Biopsy Sampling.

We herein report an 80-year-old man diagnosed with immunoproliferative small intestine disease (IPSID) via small bowel endoscopy with a biopsy. He developed persistent diarrhea and subsequently presented with hypoproteinemia and moderate anemia. Transanal double-balloon endoscopy showed prominent villous edema in the middle and lower ileum, while a histological examination showed high lymphocyte/plasma cell infiltration in the mucosal layer. Furthermore, an immunostaining analysis showed that Cluster of differentiation (CD) 3 and CD20 were partially positive, while CD138 was diffusely positive. Immunoglobulin A positivity was also observed. He was diagnosed with IPSID and received a nutritional agent and minocycline. After three months, the patients' symptoms improved.

Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy.

Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD+. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.

Biopsychological correlates of repetitive and restricted behaviors in autism spectrum disorders.

BACKGROUND: Autism Spectrum Disorder (ASD) is considered a neurodevelopmental condition that is characterized by alterations in social interaction and communication, as well as patterns of restrictive and repetitive behaviors (RRBs). RRBs are defined as broad behaviors that comprise stereotypies, insistence on sameness, and attachment to objects or routines. RRBs can be divided into lower-level behaviors (motor, sensory, and object-manipulation behaviors) and higher-level behaviors (restrictive interests, insistence on sameness, and repetitive language). According to the DSM-5, the grade of severity in ASD partially depends on the frequency of RRBs and their consequences for disrupting the life of patients, affecting their adaptive skills, and increasing the need for parental support. METHODS: We conducted a systematic review to examine the biopsychological correlates of the symptomatic domains of RRBs according to the type of RRBs (lower- or higher-level). We searched for articles from the National Library of Medicine (PubMed) using the terms: autism spectrum disorders, ASD, and autism-related to executive functions, inhibitory control, inflexibility, cognitive flexibility, hyper or hypo connectivity, and behavioral approaches. For describing the pathophysiological mechanism of ASD, we also included animal models and followed PRISMA guidelines. RESULTS: One hundred and thirty-one articles were analyzed to explain the etiology, continuance, and clinical evolution of these behaviors observed in ASD patients throughout life. CONCLUSIONS: Biopsychological correlates involved in the origin of RRBs include alterations in a) neurotransmission system, b) brain volume, c) inadequate levels of growth factors, d) hypo- or hyper-neural connectivity, e) impairments in behavioral inhibition, cognitive flexibility, and monitoring and f) non-stimulating environments. Understanding these lower- and higher-level of RRBs can help professionals to improve or design novel therapeutic strategies.

No association of HLA-DRB1 and TNF alleles in Mexican patients with autoimmune hepatitis.

HLA-DRB1 alleles has been found implicated in susceptibility to autoimmune hepatitis (AIH) in populations from different genetic backgrounds. In Mexicans, HLA-DRB1*04:04 is recognized as a risk allele for AIH but, to date, there is no high-resolution data supporting this association. Also, the association of other nonclassical HLA genes, such as TNF-LTA locus, have not, to our knowledge, been evaluated in this population. The association of HLA-DRB1 alleles determined by sequence-based typing and two polymorphisms in the TNF locus with AIH in a sample of Mexican patients was evaluated. Fifty-six patients from Guadalajara, Mexico, diagnosed with AIH and 115 age-gender matched healthy volunteer blood donors, were genotyped for HLA-DRB1 by the sequencing exon 2 and for TNFA-308G>A and LTA + 252A>G polymorphisms. Increased frequencies of both HLA-DRB1*04:04:01 and *16:02:01:01 alleles (OR = 2.91; 95% CI = 1.08-7.84) and the haplotype (DRB1-TNFA-LTA) *04:04:01-G-A (OR = 5.33; 95% CI = 1.32-21.49) were observed in AIH patients. However, after corrections for multiple comparisons, associations were not significant. In conclusion, our study does not support the association of HLA-DRB1*04:04:01 with the susceptibility to AIH in Mexican population. More studies including patients from other Mexican regions and considering other genetic, immunological, and environmental factors should be performed.

Design of a new rotating drum bioreactor operated at atmospheric pressure on the bioremediation of a polluted soil.

This paper reports the effect of the operation and design characteristics of rotating drum bioreactors (RDBs) aerated by natural convection and applied to the treatment of a soil highly polluted with weathered total petroleum hydrocarbons (TPH) (55,000 +/- 2,600 mg/kg). The parameters studied were length to diameter ratio (L/D), rotating speed (N) and lifter type. The highest TPH removal (59.6 +/- 0.7%) was obtained with the RDB of the lowest L/D ratio (1.5). Removals diminished by 27, 36 and 56%, with a ratio increment of 2.1, 3.1 and 5.1, respectively. Increment of the N, at an optimal value and lifter change from straight to helicoidal showed an improvement on the TPH removal of 20 and 30%, respectively. According to these results, slurry surface renewal through the variation of the N and the change of slurry flow was able to improve TPH removal in RDBs operated by natural convection.

Sepiapterin reductase regulation of endothelial tetrahydrobiopterin and nitric oxide bioavailability.

Sepiapterin reductase (SPR) catalyzes the final step of tetrahydrobiopterin (H(4)B) biosynthesis and the first step of H(4)B regeneration from an exogenous precursor sepiapterin. Despite the potential significance of SPR in regulating H(4)B-dependent nitric oxide (NO(*)) production, the endothelium-specific sequence and functions of SPR remain elusive. We first cloned endothelial SPR cDNA from bovine aortic endothelial cells (Genebank: DQ978331). In cells transiently transfected with SPR gene, SPR activity (HPLC) was dramatically increased by 19-fold, corresponding to a significant increase in endothelial H(4)B content (HPLC) and NO(*) production (electron spin resonance). In vivo delivery of SPR gene significantly increased vascular SPR protein expression (mouse vs. bovine antibodies to differentiate endogenous vs. exogenous), activity, H(4)B content, and NO(*) production, as well as NO(*)-dependent vasorelaxation. In endothelial cells transfected with small interfering RNA specific for SPR, approximately 87% of mRNA were attenuated (real-time quantitative RT-PCR), corresponding to a significant reduction in SPR protein expression and activity, which was associated with decreases in both intracellular H(4)B content and NO(*) level. Exogenous administration of sepiapterin to endothelial cells significantly upregulated H(4)B and NO(*) levels, which were attenuated by SPR RNA interference (RNAi). H(4)B-stimulated increase in NO(*) production, however, was SPR RNAi independent. GTP cyclohydrolase 1 expression and activity, as well as dihydrofolate reductase expression, were not affected by SPR RNAi, whereas dihydrofolate reductase activity was significantly downregulated. These data represent the first to study endothelial SPR functionally and clearly demonstrate an important role of endothelial SPR in modulating H(4)B and NO(*) bioavailability.

A technique for the removal of ureteral catheters in infants and children using a urethral sound.

PURPOSE: We report a favorable experience with an original technique in which a urethral sound was used for the extraction of Double-J ureteral catheters in infants and children. MATERIALS AND METHODS: A total of 12 children (8 females, 4 males) 6 months to 13 years old underwent extraction of a Double-J ureteral catheter under general inhalation anesthesia between March 2006 and August 2007. The catheters had been placed following pyeloplasty in 9 cases and following ureteral reimplantation in 3. Extraction was accomplished using an 8Fr, 10Fr or 12Fr urethral sound. The sound was rotated 180 degrees, thus engaging the "J" of the catheter and subsequently dragging the catheter until it emerged at the meatus. RESULTS: It was possible to extract the catheter with the sound on the first attempt in 9 cases, and on the third attempt in 3. There were no complications. CONCLUSIONS: The urethral sound may be used for easy extraction of Double-J ureteral catheters in children. The procedure may be accomplished rapidly and requires no endoscopic instruments. The technique could be of great benefit if endoscopic equipment is unavailable.

Características clínicas y hormonales del síndrome de insensibilidad a andrógenos / Clínical and hormonal characteristics of androgen insensitivity syndrome

Objetivo: Estudiar las características clínicas y hormonales de pacientes portadores del síndrome de insensibilidad a andrógenos. Material y Métodos: Se han estudiado 20 casos de pacientes portadores del síndrome de insensibilidad a andrógenos atendidos en el servicio de Endocrinología del Instituto Especializado de Salud del Niño. Se aplicó los criterios de Quigley para evaluar el grado de ambigüedad sexual.Resultados: Se encontró 10/18 (55,55%) de casos de grado III, 4/18 (22,22%) de grado IV, 2/18 (11,11%) de grado V, 1/18 (5,55%) de grado VI y 1/18 (5,55%) de grado VII, estos dos últimos grados corresponden al fenotipo femenino (SIA completo). En los pacientes con formas de SIA incompleto se encontró relación T/DHT >17, lo que equivale a discreta falla en la 5α-reductasa, lo que no sucedió con los pacientes con SIA completo. Conclusiones: El síndrome de insensibilidad a andrógenos por mostrar diversos grados de ambigüedad sexual amerita estudios genéticos, hormonales, diagnóstico por imágenes y exploración quirúrgica que permitan una orientación en la determinación del género.

Objective: Assessment of the clinical and hormonal characteristics of patients with androgen insensitivity syndrome (AIS). Materials and methods: 20 cases of AIS were studied in the Endocrinology Unit of the Instituto Especializado del Salud del Niño (Institute of Child Health - Lima, Perú). Quigley criteria was used to assess ambiguous genitalia. Results: According this criteria the findings were the following: 10/18 (55,55%) of cases were stage III, 4/18 (22,22%) were stage IV, 2/18 (11,11%) were stage V, 1/18 (5,55%) were stage VI and 1/18 (5,55%) were stage VII. The last two stages had female phenotype (complete AIS). In patients with incomplete AIS the ratio testosterone/dihydrotestosterone was less than 17, showing a mild failure of 5α-reductasa. This finding was not present in the cases with complete AIS. Conclusions: Due to the different degrees of ambiguous genitalia, the patients with AIS need genetic, hormone, images studies and surgical exploration to have the necessary criteria to suggest the most adequate therapy for each case.

Acardius acephalus. Informe de un caso y revisión de la literatura / Acardius acephalus. A case report and review of the literature

Se presenta el caso de un producto acardius acephalus gemelar de la tercera gesta, con peso de 2375 g, de término, cuyo primer gemelo se obtuvo a término, y sin malformaciones. La descripción anatómica lo incluye dentro de los productos clasificados como acárdicos amorfos, reportándose vesículas ópticas, placoda auditiva, columna vertebral incompleta, esbozos de intestino grueso, así como de tejido cerebral, duramadre y plexos coroideos. No se encontró la presencia de cavidades torácica ni abdominal. Se realizó registro, diagnóstico y clasificación del caso, con revisión de la literatura