Targeting of multiple tumor-associated antigens by individual T cell receptors during successful cancer immunotherapy.

The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A∗02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.

Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope.

We studied the prevalent cytotoxic CD8 T cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein269-277 epitope (sequence YLQPRTFLL) via the most frequent human leukocyte antigen (HLA) class I worldwide, HLA A∗02. The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as "variants of concern," was not recognized by the large CD8 T cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T cell receptors. Viral escape at prevalent T cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focused on a single protein such as SARS-CoV-2 Spike, providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T cell escape in new SARS-CoV-2 variants.

Gold Nanorod Mediated Chlorhexidine Microparticle Formation and Near-Infrared Light Induced Release.

Gold nanorods (GNR) are good light harvesting species for elaboration of near-infrared (NIR) responsive drug delivery systems. Herein, chlorhexidine microparticles are grown directly on the surface of gold nanorods and then stabilized with polyelectrolyte multilayer encapsulation, producing novel composite drug-GNR particles with high drug loading and NIR light sensitivity. Crystallization of chlorhexidine is caused by the ionic strength of the chloride solution that has been demonstrated via formation of a homogeneous porous spherical structure at 0.33 M CaCl2. By introducing GNRs into the CaCl2 solution, the nucleation of chlorhexidine molecules and size of produced spheres are affected, since GNRs act as sites for chlorhexidine nucleation. Similarly, when GNRs are replaced by chlorhexidine seeds (5.2 ± 1.7 µm), a core-shell crystal structure is observed. The encapsulated GNR/chlorhexidine composites are responsive to NIR light (840 nm) that increases the temperature at the chlorhexidine crystals, followed by microparticle dissolution and rupture of capsules which is illustrated with confocal microscopy and SEM. Furthermore, a stepwise burst release of chlorhexidine can be induced by multiple cycles of NIR light exposure. The GNR/chlorhexidine composites show good biocompatibility and antimicrobial activity. The proposed method of antibacterial drug release may therefore indicate that this NIR responsive chlorhexidine composite may be useful for future clinical applications.

Neonatal Surgical Morbidity and Mortality at a Single Tertiary Center in a Low- and Middle-Income Country: A Retrospective Study of Clinical Outcomes.

BACKGROUND: The most challenging and demanding issue in Pediatrics and Pediatric Surgery is to deal with neonatal surgery which almost always involves emergency neonatal surgical conditions. Emergency neonatal surgery most often involves congenital anomalies. More than 90% of these anomalies occur in low- and middle-income countries (LMICs) like Bangladesh. This considerable load of patients and inadequate resources in their management continue to be an unconquerable challenge for pediatric and neonatal surgeons in this region. We aim to review the challenges and constraints influencing the outcomes of emergency neonatal surgery which will guide to propose expectations from the global community. METHOD: We reviewed hospital records of neonates admitted to a tertiary care pediatric hospital between January 2016 and December 2020. Demographic and clinical data were extracted using a questionnaire and analyzed using SPSS 25. RESULTS: A total of 3,447 neonates were admitted during the five-year study period. More than 80% of the patients had at least one prenatal ultrasonography (USG) scan, but less than 10% had a prenatal diagnosis. More than 70% of the anomalies of the patient involved the gastrointestinal tract and abdominal wall. Overall mortality was an alarming 14.6%. Gastroschisis (>90%) and esophageal atresia (>85%) mainly contributed to this high mortality. The challenges detected in this review were the absence of a prenatal diagnosis, limited access to intensive care facilities, unavailability of parenteral nutrition, inadequate monitoring, and hospital-acquired sepsis. CONCLUSION: Emergency neonatal surgery contributes to a significant proportion of neonatal mortality. A holistic approach is essential to improve the situation, including the infrastructure and human resource development, identification of causes, and implementation of preventive measures to reduce the patient load. Global collaboration remains to be a vital factor to mitigate these multifactorial constraints.

Use of Spinal Anesthesia in Pediatric Laparoscopic Appendectomies: Case Series.

BACKGROUND: Owing to the widespread use of general anesthesia, administration of spinal anesthesia in pediatric patients is not widely practiced. Yet there is ample positive evidence demonstrating its safety, effectiveness, and success. OBJECTIVE: The objective of this study is to compare postoperative patient comfort, length of hospital stay, and cost-effectiveness of pediatric laparoscopic appendectomies performed under spinal and general anesthesia with the usual standard-of-care procedures employed in the hospital. METHODS: This is a case series of 77 consecutive pediatric laparoscopic appendectomies (involving 5-8-year-old children) that took place in a hospital in Chittagong, Bangladesh, in 2019. A total of 40 patients underwent spinal anesthesia and 37 patients underwent general anesthesia. Variables such as surgery and operation theater times, pain score, incidence of postsurgery vomiting, analgesic usage, discharge times, and hospital costs were recorded. Statistical analysis was used to analyze the data as a function of anesthesia type. RESULTS: The probability of vomiting when using spinal compared to general anesthesia was lower within the first 5 hours (P<.001) and 6 hours (P=.008) postoperation. A significant difference (P<.001) was observed between the total costs of the two procedures, with spinal anesthesia being less expensive. Patients were more likely to be discharged the same day of the procedure when spinal anesthesia was used (P=.008). CONCLUSIONS: Spinal anesthesia has many advantages compared to general anesthesia for pediatric laparoscopic appendectomies. Patient comfort is improved due to a significant decrease in vomiting. This allows for more rapid hospital discharges and substantial cost savings, without compromising the outcome of the procedure.

Management of Acute Appendicitis in Children During COVID-19 and Perspectives of Pediatric Surgeons From South Asia: Survey Study.

BACKGROUND: Nonoperative treatment (NOT) of pediatric appendicitis as opposed to surgery elicits great debate and is potentially influenced by physician preferences. Owing to the effects of the COVID-19 pandemic on health care, the practice of NOT has generally increased by necessity and may, in a post-COVID-19 world, change surgeons' perceptions of NOT. OBJECTIVE: The aim of this study was to determine whether the use of NOT has increased in South Asia and whether these levels of practice would be sustained after the pandemic subsides. METHODS: A survey was conducted among pediatric surgeons regarding their position, institute, and country; the number of appendicitis cases they managed; and their mode of treatment between identical time periods in 2019 and 2020 (April 1 to August 31). The survey also directly posed the question as to whether they would continue with the COVID-19-imposed level of NOT after the effect of the pandemic diminishes. RESULTS: A total of 134 responses were collected out of 200 (67.0%). A significant increase in the practice of NOT was observed for the entire cohort, although no effect was observed when grouped by country or institute. When grouped by position, senior physicians increased the practice of NOT the most, while junior physicians reported the least change. The data suggest that only professors would be inclined to maintain the COVID-19-level of NOT practice after the pandemic. CONCLUSIONS: Increased practice of NOT during the COVID-19 pandemic was observed in South Asia, particularly by senior surgeons. Only professors appeared inclined to consider maintaining this increased level of practice in the post-COVID-19 world.

Bishop Koop conversion of temporary stoma can be an option to establish gut continuity early when primary anastomosis is not safe.

Background: Intestinal perforation and sometimes obstruction in neonates demand diverting stomas which are associated with fluid, electrolytes and nutrient loss. Early establishment of gut continuity is the key to the best outcome, though primary anastomosis is not always safe. The aim of this study was to evaluate the effectiveness of Bishop Koop stoma in establishing early continuity of gut and confirming the function of distal gut. Methods: Data of patients who underwent Bishop Koop conversion of diverting stoma from July 2016 to June 2018 were reviewed retrospectively. Demographic and outcome data were recorded and analyzed using Statistical Package for the Social Science (SPSS) V.22 software. Ethical permission was taken from hospital ethical committee. Results: 29 patients were included (16 male and 13 female). Mean age of conversion was 5.8±2.5 months and mean weight was 4.9±1.6. Normal bowel movement was established in 26 patients. One patient died of sepsis on sixth postoperative day and one had anastomotic leakage. There was no significant difference with respect to outcome between perforation and obstruction group. Bishop Koop stomas were closed after 6 weeks of formation. Conclusions: Bishop Koop conversion of temporary stoma was turned out as a good choice for these patients.

Comparison of T Tube Ileostomy and Bishop Koop Ileostomy for the Management of Uncomplicated Meconium Ileus.

BACKGROUND: Meconium ileus is a common cause of neonatal intestinal obstruction. Various surgical procedures are in practice for uncomplicated meconium ileus. Bishop Koop ileostomy allows distal passage of gut content and uses the distal absorptive area. T tube ileostomy avoids the need for gut resection and formal closure of stoma. The aim of this prospective interventional study was to compare the outcome of T-tube ileostomy and Bishop Koop ileostomy for the treatment of uncomplicated meconium ileus. MATERIALS AND METHODS: It was a prospective interventional study from January 2015 to December 2016. Patients were randomly assigned to the T-tube ileostomy group (group A) and Bishop Koop ileostomy group (group B). The patients were followed up for 6 weeks post-operatively. Surgical outcomes between the two groups were compared. RESULTS: The age range of the patients was 1 to 7 days; majority of the patients were males. Mean operation time of group A (60.76±5.81 minutes) and group B (87.05±6.49 minutes) showed significant difference (p =0.0001). After operation, mean time to start bowel movements in group A (4.90±1.41days) and group B (6.53±2.58 days) showed significant difference (p= 0.020). Times to establish oral feeding, irrigation tube removal and postoperative complications showed no significant difference. All patients that survived in the group B required formal stoma closure, while in the group A stomas closed spontaneously. One patient in the group A had intraperitoneal leakage leading to mortality after second operation. Four patients had leakage in the group B; 2 of them died. CONCLUSIONS: T-tube ileostomy was found as an effective and safe procedure for the management of uncomplicated meconium ileus.

Gamma Delta (γδ) T Cells and Their Involvement in Behçet's Disease.

Behçet's disease (BD) is a multisystem inflammatory disorder characterized by orogenital ulcerations, ocular manifestations, arthritis, and vasculitis. The disease follows a relapsing-remitting course and its pathogenesis is unknown. Genetic predisposition and immune-dysregulation involving gamma delta (γδ) T cells are reported to have a role. γδ T cells are atypical T cells, which represent a small proportion of total lymphocytes. They have features of both innate and adaptive immunity and express characteristics of conventional T cells, natural killer cells, and myeloid antigen presenting cells. These unconventional T cells are found in the inflammatory BD lesions and have been suggested to be responsible for inducing and/or maintaining the proinflammatory environment characteristic of the disease. Over the last 20 years there has been much interest in the role of γδ T cells in BD. We review the literature and discuss the roles that γδ T cells may play in BD pathogenesis.

Behçet's Disease: Do Natural Killer Cells Play a Significant Role?

Behçet's disease (BD) is a complex inflammatory disease, of unknown etiology. While disease pathogenesis remains unclear, a strong relationship between BD and HLA-B*51 has been established over the last 30 years. A number of theories exist regarding the cause of BD; however, few are able to account for the increased rates of HLA-B*51 positive individuals, particularly around the Mediterranean basin and Middle-East where the prevalence is highest. This review outlines current immunogenetic data on BD and the immunoregulatory role natural killer cells may play. It also describes the interaction of the killer immunoglobulin-like receptor - KIR3DL1 with its ligand Bw4, which is found on HLA-B51. Finally, CD94/NKG2D, MICA, and ERAP are outlined with regard to their potential roles in BD.