Efficacy and safety of concurrent immune checkpoint inhibitors combined with radiotherapy or chemoradiotherapy for advanced non-small cell lung cancer: A systematic review and single-arm meta-analysis.

BACKGROUND: The recent usage of immunotherapy combined with chemoradiotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) patients. However, determining the most effective therapy combination remains a topic of debate. Research suggests immune checkpoint inhibitors (ICIs) post-chemoradiotherapy enhance survival, but the impact of concurrent ICIs during chemoradiotherapy on rapid disease progression is unclear. This meta-analysis aims to assess the effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced non-small cell lung cancer. METHODS: We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant studies, extracting data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS: The analysis included ten studies with 490 participants. Stage III NSCLC ORR was 81.8%, while Stage IV ORR was 39.9%. One-year PFS and OS for Stage III were 68.2% and 82.6%, compared to 27.9% and 72.2% for Stage IV. Common adverse events included anemia (46.6%), nausea (47.6%), rash (36.4%), and radiation pneumonitis (36.3%). CONCLUSIONS: Our meta-analysis shows concurrent ICIs with chemoradiotherapy are effective and safe in advanced NSCLC, particularly in stage III patients at risk of progression before starting ICIs after chemoradiotherapy. The findings support further phase III trials. The review protocol was registered on PROSPERO (CRD42023493685) and is detailed on the NIHR HTA programme website.

Lenvatinib plus Immune Checkpoint Inhibitors versus Lenvatinib monotherapy as treatment for advanced hepatocellular carcinoma: a meta-analysis.

Lenvatinib, an FDA-approved first-line oral multi-kinase inhibitor for advanced hepatocellular carcinoma (aHCC), has demonstrated promise for treatment. Nevertheless, findings from the Leap-002 study suggest that the addition of anti-vascular drugs to Lenvatinib may not yield significant improvements in survival rate. This meta-analysis aims to comprehensively assess the effectiveness of Lenvatinib, both as a standalone treatment and in combination with immune checkpoint inhibitors (ICIs), in managing advanced aHCC patients. We retrieved relevant studies published up to March 1, 2023, from databases such as PubMed, the Cochrane Library, Web of Science, and Embase. Subsequently, we conducted an analysis using REVMAN 5.3 and Stata MP 14.0 software, following quality assessment and data extraction procedures. A random effects model was employed to calculate the risk ratio (HR) using a 95% confidence interval (CI). The initial literature search yielded 921 results. However, after multiple rounds of exclusion and the removal of unrelated studies, 26 papers met the screening criteria. After a thorough examination of the full texts, we found that 8 studies met the analysis criteria. The combination of Lenvatinib with ICIs demonstrated significant improvement in overall survival (OS) (HR=1.53, 95% CI: 1.34-1.74; P<0.001) and progression-free survival (PFS) (HR=1.51, 95% CI: 1.34-1.72; P<0.001). Furthermore, subgroup analysis, categorized by the duration of follow-up, revealed that for the 3-year combined OS (HR=2.21, 95% CI: 1.79-2.73; Z=7.40, P<0.05), the combination therapy significantly outperformed monotherapy, leading to a 2.21-fold increase in OS for patients during the 3-year follow-up period. Nevertheless, for non-3-year combinations (HR=1.206, 95% CI: 1.020-1.425; Z=2.19, P<0.05), there was merely a 1.206-fold increase in effectiveness compared to single therapy for follow-ups of both longer and shorter durations. This might be attributed to the insufficient representation of HBV-related aHCC cases and the Asian population in the study, along with the increased availability of second-line treatment options for advanced cancer, which can influence the observed effectiveness of immunotherapy.

Femoral Neck System vs. four cannulated screws in the treatment of Pauwels III femoral neck fracture.

OBJECTIVE: To compare the clinical efficacy of the Femoral Neck System (FNS) vs. four cannulated screws in Pauwels III femoral neck fractures. METHODS: This retrospective study included patients with newly occurred type Pauwels III femoral neck fracture treated at author' Hospital of between January 2017 and February 2021. The patients received FNS (n = 27) or four cannulated screws (control group, n = 31). The operation time, blood loss, fracture healing time, incidence of complications (such as short femoral neck, necrosis of femoral head, nonunion of fracture, and failure of internal fixation withdrawal), and hip Harris score at the last follow-up were analyzed. RESULTS: The operation time, blood loss, and fracture healing time were not significantly different between the two groups (all P > 0.05). In the FNS group, three and one patients were with femoral neck shortening and femoral head necrosis, respectively, while no fracture nonunion or failure of internal fixation withdrawal occurred. In the control group, seven, two, one, and two patients were with femoral neck shortening, femoral head necrosis, nonunion, and internal fixation failure, respectively. The cumulative complication incidence was 14.8% and 38.7% in the FNS and control groups (P = 0.042). The excellent and good rates of the hip Harris score at the last follow-up were 92.6% and 71.0% in the FNS and control groups, respectively (P = 0.036). CONCLUSION: The study suggested that the clinical efficacy of FNS was better than internal fixation using four cannulated screws in treating Pauwels III type femoral neck fracture.

KDM2A plays a dual role in regulating the expression of malignancy-related genes in esophageal squamous cell carcinoma.

KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.

Effects of graphene oxide and graphene oxide quantum dots on the osteogenic differentiation of stem cells from human exfoliated deciduous teeth.

Graphene and its derivatives, graphene oxide (GO) and graphene oxide quantum dots (GOQDs), have recently attracted much attention as bioactive factors in differentiating stem cells towards osteoblastic lineage. The stem cells from human exfoliated deciduous teeth (SHEDs) possess the properties of self-renewal, extensive proliferation, and multiple differentiation potential, and have gradually become one of the most promising mesenchymal stem cells (MSCs) in bone tissue engineering. The purpose of this study was to explore the effects of GO and GOQDs on the osteogenic differentiation of SHEDs. In this study, GO and GOQDs facilitated SHED proliferation up to 7 days in vitro at the concentration of 1 µg/ml. Because of their excellent fluorescent properties, GOQD uptake by SHEDs was confirmed and distributed in the SHED cytoplasm. Calcium nodules formation, alkaline phosphatase (ALP) activity, and RNA and protein expression increased significantly in SHEDs treated with osteogenic induction medium containing GOQDs but decreased with osteogenic induction medium containing GO. Interestingly, the Wnt/ß-catenin signaling pathway appeared to be involved in osteogenic differentiation of SHEDs induced with GOQDs. In summary, GO and GOQDs at the concentration of 1 µg/ml promoted SHED proliferation. GOQDs induced the osteogenic differentiation of SHEDs, whilst GO slightly inhibited it.

Effects of cobalt chloride on the stem cell marker expression and osteogenic differentiation of stem cells from human exfoliated deciduous teeth.

Stem cells from human exfoliated deciduous teeth (SHEDs) are a promising source for tissue engineering and stem cell transplantation. However, long-term in vitro culture and expansion lead to the loss of stemness of SHEDs, compromising their therapeutic benefits. Hypoxia plays an essential role in controlling the stem cell behavior of mesenchymal stem cells (MSCs). Thus, this study aimed to investigate the effects of cobalt chloride (CoCl2), a hypoxia-mimetic agent, on the stem cell marker expression and osteogenic differentiation of SHEDs. SHEDs were cultured with or without 50 or 100 µM CoCl2. Their proliferation, apoptosis, stem cell marker expression, migration ability, and osteogenic differentiation were examined. Culture with 50 and 100 µM CoCl2 increased the hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in a dose-dependent manner in SHEDs without inducing significant cytotoxicity. This effect was accompanied by an increase in the proportion of STRO-1+ cells. CoCl2 significantly increased the expression of stem cell markers (OCT4, NANOG, SOX2, and c-Myc) in a dose-dependent manner. The migration ability was also promoted by CoCl2 treatment. Furthermore, SHEDs cultured in osteogenic medium with CoCl2 showed a dose-dependent reduction in alkaline phosphatase (ALP) activity and calcium deposition. The expression of osteogenic-related genes was also suppressed by CoCl2, especially in the 100-µM CoCl2 group. In conclusion, CoCl2 increased the expression of stem cell markers and inhibited the osteogenic differentiation of SHEDs. These findings may provide evidence supporting the use of in vitro hypoxic environments mimicked by CoCl2 in assisting the clinical application of SHEDs.

Direct radiation-induced effects on dental hard tissue.

BACKGROUND: Radiation caries is a complication of radiotherapy characterized by enamel erosion and dentin exposure. The mechanisms of characteristic radiation caries formation are not well-understood. The aim of this study was to evaluate the direct radiation-induced effects on dental hard tissue and investigate their role in the formation of radiation caries. METHODS: Sixty non-carious third molars were divided into three groups (n = 20), which would be exposed to 0 Gy, 30 Gy, and 60 Gy radiation, respectively. After radiation, microhardness and elastic modulus were measured at four depths by means of a Vickers microhardness tester and atomic force microscopy (AFM). The microstructure was observed by scanning electron microscopy (SEM). X-ray diffraction and Raman microspectroscopy were used to determine crystal properties and protein/mineral (2931/960 cm- 1) ratios. RESULTS: A statistically significant decrease in microhardness and elastic modulus values 50 µm from the dentino-enamel junction (DEJ) in enamel was revealed in the 30-Gy and 60-Gy groups. With the increasing dose, destruction of interprismatic substance and fissures at the DEJ-adjacent region were found. A greater reduction of crystallinity was revealed in enamel compared with dentin. Raman spectroscopic analysis showed a slight increase of the protein/mineral ratio for enamel following accumulated radiation, while the protein/mineral ratio for dentin was decreased. CONCLUSIONS: Radiation could directly alter the mechanical properties, micro-morphology, crystal properties, and chemical composition of dental hard tissue. The early destruction of DEJ-adjacent enamel, combined with decreased crystallinity of enamel under radiation exposure, may be related to the formation of characteristic radiation caries.

KDF1 is a novel candidate gene of non-syndromic tooth agenesis.

OBJECTIVE: Tooth agenesis (TA) is featured by congenital loss of teeth, and can be divided into two subtypes, non-syndromic TA (NSTA) and syndromic TA (STA). Although 12 candidate genes of NSTA have been revealed, the genetic basis of NSTA needs to be further studied. We noticed an overlap of candidate genes between NSTA and STA, and hypothesized that some candidate genes of STA may be new candidate genes of NSTA. METHODS: Sanger sequencing, whole exome sequencing, bioinformatics analyses and immunohistochemical staining were performed to reveal the genetic basis of the patients in a family with NSTA. RESULTS: No pathogenic mutation was found in the 12 candidate genes of NSTA. We screened the variants of 76 STA candidate genes and identified a novel pathogenic mutation c.G908C (p.R303 P) in Keratinocyte Differentiation Factor 1 (KDF1). This mutation was cosegregated with the disease in the family. Bioinformatics analyses predicted the mutation to be pathogenic. Immunohistochemical staining of kdf1 in developing tooth germs indicated that kdf1 expression is important for the development of teeth. CONCLUSIONS: This study identified KDF1 as a novel candidate gene for NSTA. STA candidate genes may be a promising source of new NSTA genes.

Clinical diagnostic value of viable Schistosoma japonicum eggs detected in host tissues.

BACKGROUND: Schistosomiasis, one of the neglected tropical diseases, is endemic in more than 70 countries. However, the clinical diagnosis of patients with a low degree of infection is an unsolved technical problem. In areas endemic for schistosomiasis japonica, proctoscopy detection of eggs has been one method used for clinical diagnosis. However, it is often a challenge to find typical live eggs and it is difficult to distinguish live eggs from large numbers of partially degraded and/or completely degraded eggs within colon biopsy tissue. To address this problem, we tested six different morphological and biochemical/molecular markers (ALP; morphological characteristics of egg; CalS (calcified substance); AOS (antioxidase); SDHG (succinic dehydrogenase) and SjR2 mRNA (retrotransposons 2 of S.japonicum genome mRNA)), including four new markers (CalS; AOS; SDHG and SjR2 mRNA.), to determine the viability of S. japonicum eggs deposited in human and mouse colon tissues. Our ultimate aim is to obtain a new method that is more sensitive, practical and accurate to clinically diagnose schistosomiasis. METHODS: Tissue samples were collected from mice at six different time points during S. japonicum infection with or without treatment with praziquantel (PZQ). Four new biochemical or molecular markers were used for the detection of egg viability from mouse liver and intestinal samples: CalS; AOS; SDHG and SjR2 mRNA. Subsequently, all markers were employed for the detection and analysis of eggs deposited in biopsy materials from patients with suspected schistosomiasis japonica for clinical evaluation. Microscopic examination of the egg morphology, worm burden in vivo and ALP (alkaline phosphatase) levels were used as a reference standard to evaluate the sensitivity and reliability of four new markers detecting egg viability. RESULTS: The results of the study showed that the morphology of S. japonicum eggs deposited in tissues of hosts with schistosomiasis, especially cases with chronic schistosomiasis, is complex and egg viability is difficult to judge morphologically, particularly eggs with a fuzzy structure or partially modified eggs. We found that the majority of the viable schistosome eggs determined by four new markers (CalS, AOS, SDHG and SjR2 mRNA) were morphologically difficult to identify. CONCLUSIONS: Among the markers, the most sensitive and specific method was the detection of SjR2 mRNA and the most simple, rapid and practical method was the detection of SDHG. Therefore, the detection of SDHG is the most practical for clinical application and its use could improve the accuracy in diagnosing active schistosome infection.

Resistance of Wheat Accessions to the English Grain Aphid Sitobion avenae.

The English grain aphid, Sitobion avenae, is a major pest species of wheat crops; however, certain varieties may have stronger resistance to infestation than others. Here, we investigated 3 classical resistance mechanisms (antixenosis, antibiosis, and tolerance) by 14 wheat varieties/lines to S. avenae under laboratory and field conditions. Under laboratory conditions, alatae given the choice between 2 wheat varieties, strongly discriminated against certain varieties. Specifically, the 'Amigo' variety had the lowest palatability to S. avenae alatae of all varieties. 'Tm' (Triticum monococcum), 'Astron,' 'Xanthus,' 'Ww2730,' and 'Batis' varieties also had lower palatability than other varieties. Thus, these accessions may use antibiosis as the resistant mechanism. In contrast, under field conditions, there were no significant differences in the number of alatae detected on the 14 wheat varieties. One synthetic line (98-10-30, a cross between of Triticum aestivum (var. Chris) and Triticum turgidum (var. durum) hybridization) had low aphid numbers but high yield loss, indicating that it has high antibiosis, but poor tolerance. In comparison, 'Amigo,' 'Xiaoyan22,' and some '186Tm' samples had high aphid numbers but low yield loss rates, indicating they have low antibiosis, but good tolerance. Aphid population size and wheat yield loss rates greatly varied in different fields and years for '98-10-35,' 'Xiaoyan22,' 'Tp,' 'Tam200,' 'PI high,' and other '186Tm' samples, which were hybrid offspring of T. aestivum and wheat related species. Thus, these germplasm should be considered for use in future studies. Overall, S. avenae is best adapted to 'Xinong1376,' because it was the most palatable variety, with the greatest yield loss rates of all 14 wheat varieties. However, individual varieties/lines influenced aphid populations differently in different years. Therefore, we strongly recommend a combination of laboratory and long-term field experiments in targeted planting regions to identify varieties/lines that consistently show high resistance to S. avenae infestation.

[Field evaluation of a novel plant molluscicide "Luo-Wei" against Oncomelania hupensis I molluscicidal effect by the spraying method in lake and marshland regions].

OBJECTIVE: To evaluate the field effect of a novel plant molluscicide "Luo-wei" (Tea-seed distilled saponins, TDS) against Oncomelania hupensis in the lake and marshland regions. METHODS: A spraying experiment was carried out in the grassland of two schistosomiasis endemic counties, including Xingzi in Jiangxi Province and the Huarong in Hunan Province, to assess the molluscicidal effect of 4% TDS comparing with 50% wettable powder of niclosamide ethanolamine salt (WPN). The chi2 test was used to examine the differences between regions, molluscicides, or days after spraying. RESULTS: Following 1, 3, 7, and 15 days of test, the snail mortality showed a simultaneous increase both in TDS group (70.43%-86.88%) and WPN group (70.21%-85.35%). There is no significant difference between TDS and WPN of day 1, 7 and 15 (all P values > 0.05), but except for day 3 (chi2 = 3.910, P = 0.048). By the end of day 15, the snail mortality for TDS was 86.53% in Xingzi and 88.28% in Huarong, while for WPN was 83.04% in Xingzi and 93.69% in Huarong respectively; the decline rate of snail density for TDS was 85.29% in Xingzi and 93.53% in Huarong, while for WPN was 85.29% in Xingzi and 93.53% in Huarong respectively. The adjusted mortality of different days ranged from 69.63% to 86.54% in the the TDS group, and 69.41% to 86.54% in the WPN group. CONCLUSION: The molluscicidal effect of TDS by spraying is similar to that of WPN. It is time to popularize this new plant molluscicide (TDS) in a wider field.

Automated home-cage behavioural phenotyping of mice.

Neurobehavioural analysis of mouse phenotypes requires the monitoring of mouse behaviour over long periods of time. In this study, we describe a trainable computer vision system enabling the automated analysis of complex mouse behaviours. We provide software and an extensive manually annotated video database used for training and testing the system. Our system performs on par with human scoring, as measured from ground-truth manual annotations of thousands of clips of freely behaving mice. As a validation of the system, we characterized the home-cage behaviours of two standard inbred and two non-standard mouse strains. From these data, we were able to predict in a blind test the strain identity of individual animals with high accuracy. Our video-based software will complement existing sensor-based automated approaches and enable an adaptable, comprehensive, high-throughput, fine-grained, automated analysis of mouse behaviour.

Efficient screening of fungal cellobiohydrolase class I enzymes for thermostabilizing sequence blocks by SCHEMA structure-guided recombination.

We describe an efficient SCHEMA recombination-based approach for screening homologous enzymes to identify stabilizing amino acid sequence blocks. This approach has been used to generate active, thermostable cellobiohydrolase class I (CBH I) enzymes from the 390 625 possible chimeras that can be made by swapping eight blocks from five fungal homologs. Constructing and characterizing the parent enzymes and just 32 'monomeras' containing a single block from a homologous enzyme allowed stability contributions to be assigned to 36 of the 40 blocks from which the CBH I chimeras can be assembled. Sixteen of 16 predicted thermostable chimeras, with an average of 37 mutations relative to the closest parent, are more thermostable than the most stable parent CBH I, from the thermophilic fungus Talaromyces emersonii. Whereas none of the parent CBH Is were active >65°C, stable CBH I chimeras hydrolyzed solid cellulose at 70°C. In addition to providing a collection of diverse, thermostable CBH Is that can complement previously described stable CBH II chimeras (Heinzelman et al., Proc. Natl Acad. Sci. USA 2009;106:5610-5615) in formulating application-specific cellulase mixtures, the results show the utility of SCHEMA recombination for screening large swaths of natural enzyme sequence space for desirable amino acid blocks.

SCHEMA recombination of a fungal cellulase uncovers a single mutation that contributes markedly to stability.

A quantitative linear model accurately (R(2) = 0.88) describes the thermostabilities of 54 characterized members of a family of fungal cellobiohydrolase class II (CBH II) cellulase chimeras made by SCHEMA recombination of three fungal enzymes, demonstrating that the contributions of SCHEMA sequence blocks to stability are predominantly additive. Thirty-one of 31 predicted thermostable CBH II chimeras have thermal inactivation temperatures higher than the most thermostable parent CBH II, from Humicola insolens, and the model predicts that hundreds more CBH II chimeras share this superior thermostability. Eight of eight thermostable chimeras assayed hydrolyze the solid cellulosic substrate Avicel at temperatures at least 5 degrees C above the most stable parent, and seven of these showed superior activity in 16-h Avicel hydrolysis assays. The sequence-stability model identified a single block of sequence that adds 8.5 degrees C to chimera thermostability. Mutating individual residues in this block identified the C313S substitution as responsible for the entire thermostabilizing effect. Introducing this mutation into the two recombination parent CBH IIs not featuring it (Hypocrea jecorina and H. insolens) decreased inactivation, increased maximum Avicel hydrolysis temperature, and improved long time hydrolysis performance. This mutation also stabilized and improved Avicel hydrolysis by Phanerochaete chrysosporium CBH II, which is only 55-56% identical to recombination parent CBH IIs. Furthermore, the C313S mutation increased total H. jecorina CBH II activity secreted by the Saccharomyces cerevisiae expression host more than 10-fold. Our results show that SCHEMA structure-guided recombination enables quantitative prediction of cellulase chimera thermostability and efficient identification of stabilizing mutations.

[Analysis on morbidity and chemotherapy effects of Schistosoma japonicum infection in fishermen on Dongting Lake].

OBJECTIVE: To clarify and evaluate the morbidity of schistosome infection and the effectiveness of chemotherapy among fishermen on East Dongting Lake. METHODS: Information on water-contact, history of infection and of praziquantel (PZQ) treatment among fishermen was collected. Kato-Katz method and miracidium hatching test were applied to detect the pathogens in stool specimen. Serum antibodies against soluble egg antigen (SEA) were detected with ELISA and IHA. B-ultrasonic examination was used to determine the pathological changes of liver and spleen. Chemotherapy [PZQ 40 mg/(kg x d)] was given to the fishermen followed by a re-examination after a transmission season. RESULTS: The first investigation (six months before chemotherapy) showed that among 268 people inquired, 90.7% were frequently or intermittently contacting water, 24.0% were treated with PZQ each year, 39.4% had never been treated in the recent five years. Stool positive rate was 68.1% (111/163) and the geometric mean eggs per gram feces (EPG) were 48.77. Males had a higher infection rate (76.0%) and intensity (62.97 EPG) compared with that of females (58.7% infection rate and 30.42 EPG). The highest positive rate (83.3%) was in the age group of 11 to 20 years old. The prevalence of those who frequently or intermittently contacted water and were never treated before was 76.3% (106/139) and 79.7% (51/64), respectively. Serological positive rate was 88.0% (IHA) or 78.7% (ELISA). B-ultrasound revealed 77.4% (82/106) of the fishermen showing pathological changes in liver and/or spleen due to schistosomiasis. 37.7% of the patients showed II-III stage liver fibrosis (male: 53.0%, female: 15%), 58.5% hepatomegaly and 19.8% splenomegaly. The second investigation (six months after chemotherapy with PZQ) showed a stool positive rate of 35.4% and an average EPG 36.13 in the treatment group which were considerably lower than 56.5% infection rate and 68.47 EPG in the group without treatment. In 39 patients treated, the reversion rate from egg positive to negative was 48.7%, pathological change in liver and spleen declined by 40.6%. CONCLUSION: The prevalence and morbidity of schistosomiasis in fishermen on Dongting Lake were high due to frequent exposure to the affected water, and chemotherapy can effectively reduce the prevalence, the intensity of infection and morbidity of the fishermen.