Birth Weight, Infant Growth, and Childhood Body Mass Index: Hong Kong’s Children of 1997 Birth Cohort

ObjectiveTo investigate the association between birth weight, infant growth rate, and childhood adiposity as a proxy for adult metabolic or cardiovascular risk in a Chinese population with a history of recent and rapid economic development. DesignProspective study in a population-representative birth cohort. SettingHong Kong Chinese population. ParticipantsSix thousand seventy-five term births (77.5% successful follow-up). Main ExposuresBirth weight and growth rate (change in the weight z score) at ages 0 to 3 and 3 to 12 months. Main Outcome Measure: Body mass index (BMI) (calculated as the weight in kilograms divided by the height in meters squared) z score at about age 7 years. ResultsEach unit increase in the weight z score at ages 0 to 3 and 3 to 12 months increased the BMI z score by 0.52 and 0.33, respectively. Children in the highest birth weight and growth rate tertiles had the highest BMI z scores. In the lowest birth weight tertile, increases in the weight z score at ages 0 to 3 months had a larger effect on the BMI z score in boys (mean difference, 0.88; 95% confidence interval 0.69-1.07) than in girls (mean difference, 0.52; 95% confidence interval, 0.33-0.71); these differences by birth weight, growth rate at ages 0 to 3 months, and sex were significant (P=.007). Conclusions Faster prenatal and postnatal growth were associated with higher childhood BMI in a population with a recent history of rapid economic growth and relatively low birth weight, suggesting that maximal growth may not be optimal for metabolic risk. However, there may be a developmental trade-off between metabolic risk and other outcomes

Multimodal Integrative Genomics and Pathology Analyses in Neoadjuvant Nivolumab Treatment for Intermediate and Locally Advanced Hepatocellular Carcinoma

Introduction: Immunotherapy has resulted in pathologic responses in hepatocellular carcinoma (HCC), but the benefits and molecular mechanisms of neoadjuvant immune checkpoint blockade are largely unknown. Methods: In this study, we evaluated the efficacy and safety of preoperative nivolumab (anti-PD-1) in patients with intermediate and locally advanced HCC and determined the molecular markers for predicting treatment response. Results: Between July 2020 and November 2021, 20 treatment-naive HCC patients with intermediate and locally advanced tumors received preoperative nivolumab at 3 mg/kg for 3 cycles prior to surgical resection. Nineteen patients underwent surgical resection on trial. Seven (36.8%) of the 19 patients had major pathologic tumor necrosis (≥60%) in the post-nivolumab resection specimens, with 3 having almost complete (>90%) tumor necrosis. The tumor necrosis was hemorrhagic and often accompanied by increased or dense immune cell infiltrate at the border of the tumors. None of the patients developed major adverse reactions contradicting hepatectomy. RNA-sequencing analysis on both pre-nivolumab tumor biopsies and post-nivolumab resected specimens showed that, in cases with major pathologic necrosis, the proportion of CD8 T cells in the HCC tissues predominantly increased after treatment. Moreover, to investigate noninvasive biomarker for nivolumab response, we evaluated the copy number variation (CNV) using target-panel sequencing on plasma cell-free DNA of the patients and derived a CNV-based anti-PD-1 score. The score correlated with the extent of tumor necrosis and was validated in a Korean patient cohort with anti-PD-1 treatment. Conclusion: Neoadjuvant nivolumab demonstrated promising clinical activity in intermediate and locally advanced HCC patients. We also identified useful noninvasive biomarker predicting responsiveness

Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma

Purpose: To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). Methods and Materials: All patients were irradiated with the same RT technique to ≥66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil). Results: Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (p ≥ 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p < 0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05). Conclusions: Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted. © 2006 Elsevier Inc. All rights reserved.Link_to_subscribed_fulltex

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field