Autologous umbilical cord blood infusion for the treatment of autism in young children: A within-subjects open label study on safety (assessed via caregiver report) and efficacy.

This study aimed to document the safety and efficacy of a single infusion of autologous umbilical cord blood (UCB) in 20 autistic children aged 24-72 months. A pre-post treatment within-subjects open label design was used. At T = 0, 6, 12, and 18 months, participants underwent detailed and structured safety evaluations (via caregiver report), Vineland Adaptive Behavior Scale (Vineland-3), Stanford Binet Intelligence Scale (SB-5), Expressive One-Word Picture Vocabulary Test, Brief Observation of Social Communication Change (BOSCC), Pervasive Developmental Disorder-Behavior Inventory, Repetitive Behavior Scale-Revised, Sensory Experience Questionnaire (SEQ-2.1), Child Behavior Checklist, Clinical Global Impression-Severity and Improvement (CGI-I) Scales, and eye-gaze tracking. UCB infusion was conducted at T = 6 months, hence, 0-6 months was the control period, and 6-18 months the follow-up period. Of 20 children recruited, 19 completed the study and 1 was withdrawn due to UCB not meeting quality control criteria for infusion. There were 15 males and 4 females with an overall mean (SD) age of 4.15 (0.62) years. Mean (SD) cell dose administered was 38.16 (9.82) million cells/kg. None suffered serious adverse events although there were mild behavioral side effects and one unit grew coagulase negative staphylococcus from a post-thaw sample. There were no significant differences in Vineland-3, SB-5, BOSCC, and SEQ-2.1 scores at T = 12 and T = 18 months. Twelve participants had T = 18 CGI-I scores of 2-3 (minimally to much improved), seven participants had scores of 4 (no change). Autologous UCB infusion in autistic children is generally safe but not without risks, including that of infection. In this within-subjects study, some children showed global symptom improvements while others showed no change. Stem cell therapies for autism should only be conducted under strict clinical trial conditions with clear risk discussions.

A Case of Posttransplant Fibrillary Glomerulonephritis.

Fibrillary glomerulonephritis (FGN) is a rare form of glomerulonephritis, usually occurring in concurrence with other conditions such as hepatitis C, dysproteinemia, autoimmune conditions, diabetes mellitus, and malignancy. The diagnosis is made by the presence of randomly oriented fibrillar deposits with a mean diameter of 20 nm, which stain positive for IgG and C3 and are negative for congo red and thioflavin T stains. Staining for DNAJB9 (DnaJ homolog subfamily B member 9) is a recently discovered mode of diagnosis of FGN without electron microscopy. The prognosis is poor and optimal treatment is yet not clearly defined, though rituximab may be useful in FGN patients with relatively preserved renal functions. In this case report, we discuss a case of post-renal transplant patient with de novo occurrence of fibrillary glomerulonephritis.

Alloimmune Neutropenia in a Neonate: Case Report and Review of Literature.

Neonatal alloimmune neutropenia, variably referred to in the literature as NAIN, FNAIN or NIN, is a disorder of neutrophil destruction in newborns similar to better-known conditions such as hemolytic disease of the newborn and neonatal alloimmune thrombocytopenia (FNAIT). Infants affected by this self-limiting condition can present asymptomatically or have a wide range of symptoms, from skin manifestations and mucositis to severe infections such as sepsis and pneumonia. In our case, we report an otherwise asymptomatic term infant born with severe neutropenia to a mother affected by COVID-19 in the 3rd trimester. However, it is unclear if COVID-19 contributed to our patients' neutropenia. Diagnostic testing eventually revealed the presence of anti-neutrophil antibodies, confirming the diagnosis of alloimmune neutropenia. The infant was conservatively managed with early discharge prior to resolution of neutropenia and close post-discharge follow up.

Human leukocyte antigen allele and haplotype frequencies in Singapore bone marrow donors and cord blood units.

We describe the allele and haplotype frequencies seen in a volunteer unrelated bone marrow donor registry, a public cord blood bank, and donor/recipient samples processed by the Health Sciences Authority (HSA) in Singapore. Historical human leukocyte antigen (HLA) typing reports were anonymized and combined. They were checked for HLA typing nomenclature discrepancies or ambiguities using the HLA-net UNIFORMATE tool, and for analysis, the validated data were subsequently separated into Chinese, Malay, Indian, and "Others," according to the race classification system used in Singapore. Individual ethnic allele and haplotype frequencies were calculated with the HLA-net GENE[RATE] pipeline using basic statistics. The Basic Statistics Tool of HLA-net was used to estimate haplotype frequency using an expectation maximization algorithm, given a set of multi-allelic data pairs for a given HLA locus. The outputs downloaded from the site comprised plain text files with haplotype frequency estimates, results of a global linkage disequilibrium test, and standardized residuals (stdres) corresponding to deviations from expected frequencies. HLA typing results from 59,186 individuals met the inclusion criteria, yielding 118,372 analyzable alleles. In our study population, the haplotype A*33:03-B*58:01-C*03:02-DRB1*03:01～DQB1*02:01:01G with a frequency of 4.91% was the most common. This haplotype was also the most common among Singaporean Chinese donors. Consistent with the predominant Chinese population, haplotypes with a frequency greater than 1% were also the most frequently observed haplotypes in the Singaporean population. In the Malay donor population, the most common haplotype was A*33:03～B*44:03～C*07:01:01G～ DRB1*07:01-DQB1*02:01:01G, with a frequency of 3.41%, whereas within the Indian donor population, the most common haplotype was A*01:01-B*57:01-C*06:02～DRB1*07:01-DQB1*03:03, with a frequency of 3.42%. Haplotype diversity and composition statistics within donor pools provide HLA background data required for the targeted recruitment of donors to support the hematopoietic stem cell donor requirements of the country. These data may be used in the future to devise donor recruitment strategies for optimizing the donor pool through targeted publicity and accruals.

Schwartz Jampel Syndrome (SJS)-One in a Million Syndrome.

Schwartz Jampel syndrome is a very rare genetically heterogenous disorder characterized by myotonia, typical facies, growth retardation and osteoarticular changes. Prevelance of this syndrome is <1 in 100000. 150 cases have been reported in medical literature so far. We hereby report this rare syndrome in neurology.

Nanoparticles' interactions with vasculature in diseases.

The ever-growing use of inorganic nanoparticles (NPs) in biomedicine provides an exciting approach to develop novel imaging and drug delivery systems, owing to the ease with which these NPs can be functionalized to cater to various applications. In cancer therapeutics, nanomedicine generally relies on the enhanced permeability and retention (EPR) effect observed in tumour vasculature to deliver anti-cancer drugs across the endothelium. However, such a phenomenon is dependent on the tumour microenvironment and is not consistently observed in all tumour types, thereby limiting drug transport to the tumour site. On the other hand, there is a rise in utilizing inorganic NPs to intentionally induce endothelial leakiness, creating a window of opportunity to control drug delivery across the endothelium. While this active targeting approach creates a similar phenomenon compared to the EPR effect arising from tumour tissues, its drug delivery applications extend beyond cancer therapeutics and into other vascular-related diseases. In this review, we summarize the current findings of the EPR effect and assess its limitations in the context of anti-cancer drug delivery systems. While the EPR effect offers a possible route for drug passage, we further explore alternative uses of NPs to create controllable endothelial leakiness within short exposures, a phenomenon we coined as nanomaterial-induced endothelial leakiness (NanoEL). Furthermore, we discuss the main mechanistic features of the NanoEL effect that make it unique from conventionally established endothelial leakiness in homeostatic and pathologic conditions, as well as examine its potential applicability in vascular-related diseases, particularly cancer. Therefore, this new paradigm changes the way inorganic NPs are currently being used for biomedical applications.

Small Cell Carcinoma of Anal Canal - A Rare Case Report.

Anal canal malignancy is one of the dreadful conditions. Most of the anal canal malignancies are squamous cell carcinomas for which the treatment is well established and the prognosis is usually favourable. Small cell carcinoma of anal canal is a very rare condition and poorly understood, which can present as haemorrhoids in its early stages and has an aggressive course. We present a case of small cell carcinoma of anal canal who underwent Abdomino Perineal Resection (APR) and chemotherapy. He developed liver metastasis during the course of chemotherapy and succumbed to the condition 4 months later.

Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity.

Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine.

Inhibition of rapamycin-induced AKT activation elicits differential antitumor response in head and neck cancers.

The PI3K/AKT/mTOR pathway is an important signaling axis that is perturbed in majority of cancers. Biomarkers such as pS6RP, GLUT1, and tumor FDG uptake are being evaluated in patient stratification for mTOR pathway inhibitors. In the absence of a clear understanding of the underlying mechanisms in tumor signaling, the biomarker strategy for patient stratification is of limited use. Here, we show that no discernible correlation exists between FDG uptake and the corresponding Ki67, GLUT1, pS6RP expression in tumor biopsies from patients with head and neck cancer. Correlation between GLUT1 and pS6RP levels in tumors was observed but elevated pS6RP was noticed even in the absence of concomitant AKT activation, suggesting that other downstream molecules of PI3K/AKT and/or other pathways upstream of mTOR are active in these tumors. Using an ex vivo platform, we identified putative responders to rapamycin, an mTOR inhibitor in these tumors. However, rapamycin did not induce antitumor effect in the majority of tumors with activated mTOR, potentially attributable to the observation that rapamycin induces feedback activation of AKT. Accordingly, treatment of these tumors with an AKT inhibitor and rapamycin uniformly resulted in abrogation of mTOR inhibition-induced AKT activation in all tumors but failed to induce antitumor response in a subset. Phosphoproteomic profiling of tumors resistant to dual AKT/mTOR inhibitors revealed differential activation of multiple pathways involved in proliferation and survival. Collectively, our results suggest that, in addition to biomarker-based segregation, functional assessment of a patient's tumor before treatment with mTOR/AKT inhibitors may be useful for patient stratification.

Nonhuman primate allogeneic hematopoietic stem cell transplantation by intraosseus vs intravenous injection: Engraftment, donor cell distribution, and mechanistic basis.

OBJECTIVE: The traditional intravenous (IV) route of administration for hematopoietic stem cell transplantation (HSCT) may result in inefficient placement of donor cells, possibly contributing to suboptimal engraftment and higher risk of graft-vs-host reactions. In order to perform detailed studies of engraftment and donor cell distribution in an animal model with anatomical similarity to man, we performed the first direct homing/engraftment efficiency comparison between intraosseus (IO) and IV HSCT in allogeneic nonhuman primate animal model to assess the utility and mechanism of donor cell homing after IO delivery. MATERIALS AND METHODS: Donor bone marrow (BM) cells labeled with PKH26 membrane dye were transplanted to nonmyeloablative-conditioned nonhuman primate animals. Chimerism was confirmed by polymerase chain reaction amplification of donor-specific short tandem repeat locus. RESULTS: Compared to the IO route, IV infusion trapped 2.4- to 4.8-fold more donor cells in peripheral organs, including the lung, heart, spleen, kidney, and liver. IO injection resulting in a 6.2-fold increase in donor cells retained in the BM at the site of injection and a 2.7-fold increase in donor cells retained in distant BM sites. A profile of selected cell adhesion molecules (CAMs) demonstrated that after IO HSCT, more donor cells express CAMs that could facilitate BM homing and redistribution to non-injection-side BM cavities. This change in homing efficiency may be clinically significant because IO transplantation in haploidentical recipients enhanced donor cell engraftment when compared to IV delivery. CONCLUSION: Our results suggest that IO injection enhances both homing and engraftment in nonhuman primate HSCT.