Advances in immunotherapy for triple-negative breast cancer.

BACKGROUND: Immunotherapy has recently emerged as a treatment strategy which stimulates the human immune system to kill tumor cells. Tumor immunotherapy is based on immune editing, which enhances the antigenicity of tumor cells and increases the tumoricidal effect of immune cells. It also suppresses immunosuppressive molecules, activates or restores immune system function, enhances anti-tumor immune responses, and inhibits the growth f tumor cell. This offers the possibility of reducing mortality in triple-negative breast cancer (TNBC). MAIN BODY: Immunotherapy approaches for TNBC have been diversified in recent years, with breakthroughs in the treatment of this entity. Research on immune checkpoint inhibitors (ICIs) has made it possible to identify different molecular subtypes and formulate individualized immunotherapy schedules. This review highlights the unique tumor microenvironment of TNBC and integrates and analyzes the advances in ICI therapy. It also discusses strategies for the combination of ICIs with chemotherapy, radiation therapy, targeted therapy, and emerging treatment methods such as nanotechnology, ribonucleic acid vaccines, and gene therapy. Currently, numerous ongoing or completed clinical trials are exploring the utilization of immunotherapy in conjunction with existing treatment modalities for TNBC. The objective of these investigations is to assess the effectiveness of various combined immunotherapy approaches and determine the most effective treatment regimens for patients with TNBC. CONCLUSION: This review provides insights into the approaches used to overcome drug resistance in immunotherapy, and explores the directions of immunotherapy development in the treatment of TNBC.

Structural Basis for the Broad, Antibody-Mediated Neutralization of H5N1 Influenza Virus.

Human infection with highly pathogenic avian influenza A viruses causes severe disease and fatalities. We previously identified a potent and broadly neutralizing antibody (bnAb), 13D4, against the H5N1 virus. Here, we report the co-crystal structure of 13D4 in complex with the hemagglutinin (HA) of A/Vietnam/1194/2004 (H5N1). We show that heavy-chain complementarity-determining region 3 (HCDR3) of 13D4 confers broad yet specific neutralization against H5N1, undergoing conformational rearrangement to bind to the receptor binding site (RBS). Further, we show that mutating four critical residues within the RBS-Trp153, Lys156, Lys193, and Leu194-disrupts the binding between 13D4 and HA. Viruses bearing Asn193 instead of Lys/Arg can evade 13D4 neutralization, indicating that Lys193 polymorphism might be, at least in part, involved in the antigenicity of recent H5 genotypes (such as H5N6 and H5N8) as distinguished from H5N1. BnAb 13D4 may offers a template for therapeutic RBS inhibitor design and serve as an indicator of antigenic change for current H5 viruses.IMPORTANCE Infection by highly pathogenic avian influenza A virus remains a threat to public health. Our broadly neutralizing antibody, 13D4, is capable of neutralizing all representative H5N1 viruses and protecting mice against lethal challenge. Structural analysis revealed that 13D4 uses heavy-chain complementarity-determining region 3 (HCDR3) to fit the receptor binding site (RBS) via conformational rearrangement. Four conserved residues within the RBS are critical for the broad potency of 13D4. Importantly, polymorphism of Lys193 on the RBS may be associated with the antigenicity shift from H5N1 to other newly emerging viruses, such as H5N6 and H5N8. Our findings may pave the way for highly pathogenic avian influenza virus vaccine development and therapeutic RBS inhibitor design.

Occurrence, Distribution, and Potential Sources of Organophosphate Esters in Urban and Rural Surface Water in Shanghai, China.

In this study, the occurrence and distribution patterns of eight organophosphate esters (OPEs) were investigated in urban and rural surface water in a typical cosmopolitan city: Shanghai, China. In addition, concentration levels and removal efficiencies of seven sewage treatment plants were analyzed. The OPEs concentrations detected in urban rivers were significantly higher than those detected in rural rivers. Total OPEs ranged from 185.4 to 321 ng L-1 in rural surface water and from 340 to 1688.7 ng L-1 in urban, with an average of 221.8 ng L-1 and 850.2 ng L-1, respectively. Compared with other studies published in the world, the OPEs contamination in surface river water in Shanghai was at a moderate level. Furthermore, the potential sources of OPEs in urban surface water were investigated, and the results indicated that OPEs in urban surface water mainly came from three potential sources. In rural surface water, the OPE concentrations were uniformly distributed, so OPEs in rural surface water may came from nonpoint source pollution. Last, a preliminary environmental risk assessment and health risk assessment were conducted. The results showed low environmental risks at all sampling sites (except for sampling point R7: medium risk for algae) for the three aquatic organisms (algae, daphnia, and fish). Health risk assessment indicated a noncarcinogenic risk for diverse human groups for Æ©OPEs.

Rs4938723 Polymorphism Is Associated with Susceptibility to Hepatocellular Carcinoma Risk and Is a Protective Factor in Leukemia, Colorectal, and Esophageal Cancer.

BACKGROUND Growing evidence indicates that a non-coding RNA named miR-34b/c plays crucial roles in carcinogenesis, and its common polymorphism, pri-miR-34b/c rs4938723, also participates in this process and is associated with cancer susceptibility. However, this association was previously undefined and ambiguous. Therefore, we carried out an updated analysis to evaluate this relationship between rs4938723 polymorphism and cancer susceptibility. MATERIAL AND METHODS PubMed, EMbase, Web of Science and Chinese language (WanFang, CNKI and VIP) databases were searched for relevant studies until Sep 10, 2018. Odds ratios and 95% confidence interval were applied to assess this relationship. RESULTS Thirty case-control studies were retrieved. No positive association was found in either the overall study population or in the subgroups, based on ethnicity, source of group, sex, smoking, and drinking status. The main results were observed in the stratified analysis subgroups in cancer type subgroup: rs4938723 polymorphism may be a protective factor in leukemia, colorectal cancer, and esophageal cancer; however, C-allele was a risk factor in carriers for hepatocellular carcinoma. Last but not the least, poor positive results were discovered in the age subgroup. CONCLUSIONS Current meta-analysis suggested that rs4938723 polymorphism was potentially associated with hepatocellular carcinoma risk, but this polymorphism had a decreased association for susceptibility to esophageal cancer, leukemia, and colorectal cancer. Furthermore, studies with larger sample sizes and including gene-gene or gene-environment interactions should be carried out to elucidate the role of rs4938723 polymorphism in cancer risk.

Bone marrow mesenchymal stem cell transplantation improves radiation-induced heart injury through DNA damage repair in rat model.

Radiotherapy is an effective form of therapy for most thoracic malignant tumors. However, myocardial injury resulting from the high doses of radiation is a severe complication. Here we aimed to study the possibility of reducing radiation-induced myocardial injury with mesenchymal stem cell (MSC) transplantation. We used MSCs extracted from bone marrow (BMSCs) to transplant via the tail vein into a radiation-induced heart injury (RIHI) rat model. The rats were divided into six groups: a Sham group, an IRR (irradiation) group, and four IRR + BMSCs transplantation groups obtained at different time points. After irradiation, BMSC transplantation significantly enhanced the cardiac function in rats. By analyzing the expression of PPAR-α, PPAR-γ, TGF-ß, IL-6, and IL-8, we found that BMSC transplantation alleviated radiation-induced myocardial fibrosis and decreased the inflammatory reaction. Furthermore, we found that expression of γ-H2AX, XRCC4, DNA ligase4, and TP53BP1, which are associated with DNA repair, was up-regulated, along with increased secretion of growth factors SDF-1, CXCR4, VEGF, and IGF in rat myocardium in the IRR + BMSCs transplantation groups compared with the IRR group. Thus, BMSC transplantation has the potential to improve RIHI via DNA repair and be a new therapeutic approach for patients with myocardial injury.

Posterior scleral reinforcement combined with patching therapy for pre-school children with unilateral high myopia.

PURPOSE: Our purpose was to investigate the effect of posterior scleral reinforcement (PSR) combined with patching therapy for pre-school children with unilateral high myopia. METHODS: A total of 32 pre-school children with unilateral high myopia were recruited. They were randomly divided into the PSR and control group, each of which had 16 patients. The patients in the PSR group underwent the simplified PSR surgery followed by rigid gas permeable contact lens wear and traditional patching therapy, while the patients in the control group were only prescribed contact lens wear and patching. Patients were reviewed and the axial length, refraction, best-corrected visual acuity, and stereoscopic vision were respectively examined postoperatively at yearly intervals for three years. RESULTS: The best-corrected visual acuity was significantly higher in the PSR group than that in the control group at any study visit. A statistically significant difference in axial length was found between the PSR group (27.38 ± 1.30 mm) and the control group (28.29 ± 0.74 mm) at the postoperative three-year (p = 0.03) time point. There was a statistical difference in refractive error between the PSR group (-13.13 ± 2.55 D) and the control group (-15.42 ± 1.83 D) at 3-year follow-up. No significant difference was found between the two groups with respect to the stereoscopic vision by the end of follow-up at 3 years (p =0.103). CONCLUSIONS: PSR combined with the patching therapy has the potential to arrest the progression of high myopia and to help the treatment for amblyopia.

Refractive change in the adult rabbit eye after corneal relaxation with the femtosecond laser.

BACKGROUND: A new procedure to correct myopia that does not disturb the cornea in the optical zone and avoids injuring the corneal epithelium could be a key advance in corneal refractive surgery. The aim of this study is to observe the refractive change in the adult rabbits undergoing femtosecond laser-assisted multilayer intrastromal ablation in the mid-periphery of the cornea without injury of epithelium. METHOD: The right eyes of 8 New Zealand White adult rabbits were used for the experiments. A 60-kHz femtosecond laser delivery system was used, and three lamellar layers of laser pulses were focused starting at a corneal depth of 180 µm and ending at 90 µm from the surface, with each successive layer placed 45 µm anterior to the previous layer. In the interface of the applanation contact lens cone, a 6-mm diameter aluminum circle was placed at the center to block the laser, limiting ablation to the mid-periphery of the cornea. The laser settings were as follows: spot/line separation, 10 µm; diameter, 8.0 mm; energy for ablating the stroma, 1.3 µJ. An authorefractor was used to assess the manifest refraction. RESULTS: Mean spherical equivalent (SE) (mean ± SD, SD: standard deviation) was significantly increased at postoperative week 1 (1.67 ± 0.26 D, p < 0.0001), month 1 (1.65 ± 0.23 D, p < 0.0001), and month 3 (1.60 ± 0.22 D, p < 0.0001) compared to baseline (0.68 ± 0.27 D). Mean spherical equivalent showed no significant change between postoperative week 1 and month 3 (p = 0.1168). CONCLUSION: Femtosecond laser-assisted multilayer corneal intrastromal ablation in the mid-periphery may cause a consequent hyperopic shift with no refractive regression.

Screening of Burkholderia sp. WGB31 producing anisic acid from anethole and optimization of fermentation conditions.

Anisic acid, the precursor of a variety of food flavors and industrial raw materials, can be bioconversed from anethole which extracted from star anise fruits. WGB31 strain with anisic acid molar production rate of 10.25% was isolated and identified as Burkholderia sp. Three significant influential factors, namely, glucose concentration, initial pH value, and medium volume were selected and their effects were evaluated by Box-Behnken Design (BBD). Regression analysis was performed to determine response surface methodology and the significance was tested to obtain the process model of optimal conditions for producing anisic acid. The fermentation conditions at the stable point of the model were obtained: glucose 6 g L(-1) , pH 6.2, culture medium volume 61 mL in a triangular flask with 250 ml volume. Verification test indicated that the production rate of anisic acid was 30.7%, which was three times of that before optimizing. The results provide a basis and reference for producing anisic acid by microbial transformation.

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot.

Immunotherapy has emerged as a promising cancer treatment option in recent years. In immune "hot" tumors, characterized by abundant immune cell infiltration, immunotherapy can improve patients' prognosis by activating the function of immune cells. By contrast, immune "cold" tumors are often less sensitive to immunotherapy owing to low immunogenicity of tumor cells, an immune inhibitory tumor microenvironment, and a series of immune-escape mechanisms. Immunogenic cell death (ICD) is a promising cellular process to facilitate the transformation of immune "cold" tumors to immune "hot" tumors by eliciting innate and adaptive immune responses through the release of (or exposure to) damage-related molecular patterns. Accumulating evidence suggests that various traditional therapies can induce ICD, including chemotherapy, targeted therapy, radiotherapy, and photodynamic therapy. In this review, we summarize the biological mechanisms and hallmarks of ICD and introduce some newly discovered and technologically innovative inducers that activate the immune system at the molecular level. Furthermore, we also discuss the clinical applications of combing ICD inducers with cancer immunotherapy. This review will provide valuable insights into the future development of ICD-related combination therapeutics and potential management for "cold" tumors.

Role of tumor-derived exosomes mediated immune cell reprograming in cancer.

Tumor-derived exosomes (TDEs), as topologies of tumor cells, not only carry biological information from the mother, but also act as messengers for cellular communication. It has been demonstrated that TDEs play a key role in inducing an immunosuppressive tumor microenvironment (TME). They can reprogram immune cells indirectly or directly by delivering inhibitory proteins, cytokines, RNA and other substances. They not only inhibit the maturation and function of dendritic cells (DCs) and natural killer (NK) cells, but also remodel M2 macrophages and inhibit T cell infiltration to promote immunosuppression and create a favorable ecological niche for tumor growth, invasion and metastasis. Based on the specificity of TDEs, targeting TDEs has become a new strategy to monitor tumor progression and enhance treatment efficacy. This paper reviews the intricate molecular mechanisms underlying the immunosuppressive effects induced by TDEs to establish a theoretical foundation for cancer therapy. Additionally, the challenges of TDEs as a novel approach to tumor treatment are discussed.

Gfi-1 modulates HMGB1-Mediated autophagy to overcome oxaliplatin resistance in colorectal cancer.

Background: Resistance to oxaliplatin (L-OHP) is a major barrier in the treatment of colorectal cancer (CRC). Autophagy is the main cause of L-OHP tolerance in CRC cells. Method: The human colon cancer cell lines HCT116 and SW480 were treated with L-OHP to obtain the drug-resistant cell lines HCT116/L-OHP and SW480/L-OHP, respectively. To probe the relationship between autophagy and L-OHP tolerance of growth factor independent 1 (Gfi-1) and high-mobility group protein 1 (HMGB1) in CRC cells, gene knockout or overexpression was performed, and Western blotting was used to determine the levels of drug tolerance interrelated proteins. Transwell and CCK-8 assays were employed to analyze the proliferation of cancer cells. Immunofluorescence detection of LC3 reflected autophagy levels. Finally, the relationship between Gfi-1 and HMGB1 was detected by chromatin immunoprecipitation (ChIP). Result: Compared to normal CRC cells, L-OHP-tolerant CRC cells exhibited greater autophagy (8.2 times greater in HCT116/L-OHP cells and 7.4 times greater in SW480/L-OHP cells). In addition, we detected low levels of Gfi-1 (0.6-fold for HCT116/L-OHP cells and 0.4-fold for SW480/L-OHP cells), and OE-Gfi-1 decreased HMGB1 levels (0.6-fold for HCT116/L-OHP + OE-Gfi-1 cells and 0.5-fold for SW480/L-OHP + OE-Gfi-1 cells). The inhibition of Gfi-1 further enhanced cell viability (1.7 times in HCT116+sh-Gfi-1 cells and 1.2 times in SW480+sh-Gfi-1 cells) and invasion (1.8 times in HCT116+sh-Gfi-1 cells and 2.1 times in SW480+sh-Gfi-1 cells) in CRC cells, thus promoting oxaliplatin resistance in these cells. The autophagy inhibitor 3-MA reversed the above effects. Furthermore, we noted that Gfi-1 can restrain HMGB1 expression by binding to its promoter (0.5 times in HCT116+OE-Gfi-1 cells and 0.5 times in SW480+OE-Gfi-1 cells). The inhibitory influence of 3-MA on HMGB1 reversed the influence of Gfi-1 on autophagy and malignant progression in CRC cells. Conclusion: Our study suggested that Gfi-1 inhibited HMGB1 to reduce CRC autophagy levels, increasing CRC sensitivity to L-OHP.

Zuogui pill disrupt the malignant cycle in breast cancer bone metastasis through the Piezo1-Notch-1-GPX4 pathway and active molecules fishing.

BACKGROUND: Breast cancer bone metastasis is closely associated with the bone microenvironment. Zuogui Pill (ZGP), a clinically approved formulation in China, effectively regulates the bone microenvironment for the prevention and treatment of osteoporosis. PURPOSE: Few reports have utilized the ZGP for bone metastasis models. This study investigated the intervention and bone-protective properties of ZGP against breast cancer bone metastasis, explored the potential mechanism, and screened for its active compositions by molecules fishing. METHODS: To investigate the intervention efficacy of ZGP and its protein-level mechanism of action, the mouse bone metastasis model and in vitro cell co-culture model were constructed. Affinity ultrafiltration, molecular docking, cellular thermal shift assay and physical scale detection were used to investigate the affinity components of the RANKL protein in ZGP. RESULTS: The administration of ZGP combined with zoledronic acid inhibited the development of tumors and secondary lung metastasis in mice. This translated to a prolonged survival period and enhanced quality of life. ZGP could disrupt the malignant cycle by modulating the Piezo1-Notch-1-GPX4 signaling pathway in the "bone-cancer" communication in the cell co-culture model. Furthermore, 25 chemical components of ZGP were identified, with 10 active compounds exhibiting significant affinity for the RANKL protein. CONCLUSION: The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.

Creatinine-to-cystatin C ratio and body composition predict response to PD-1 inhibitors-based combination treatment in metastatic gastric cancer.

Background: Creatinine-to-cystatin C ratio (CCR) and body composition (BC) parameters have emerged as significant prognostic factors in cancer patients. However, the potential effects of CCR in gastric cancer (GC) remains to be elucidated. This multi-center retrospective study explored the predictive and prognostic value of CCR and BC-parameters in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy. Methods: One hundred and thirteen GC patients undergoing PD-1 inhibitors-based combination therapy were enrolled at three academic medical centers from January 2021 to July 2023. A deep-learning platform based on U-Net was developed to automatically segment skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI). Patients were divided into two groups based on the median of CCR or the upper tertile of BC-parameters. Logistic and Cox regression analysis were used to determine the effect of CCR and BC-parameters in predicting response rates and survival rates. Results: The CCR was positively correlated with SMI (r=0.43; P<0.001), but not with SATI or VATI (P>0.05). Multivariable logistic analysis identified that both low CCR (OR=0.423, P=0.066 for ORR; OR=0.026, P=0.005 for DCR) and low SATI (OR=0.270, P=0.020 for ORR; OR=0.149, P=0.056 for DCR) were independently associated with worse objective response rate (ORR) and disease control rate (DCR). Patients with low CCR or low SATI had significantly lower 8-month progression-free survival (PFS) rate and 16-month overall survival (OS) rate than those with high CCR (PFS rate, 37.6% vs. 55.1%, P=0.011; OS rate, 19.4% vs. 44.9%, P=0.002) or those with high SATI (PFS rate, 37.2% vs. 53.8%, P=0.035; OS rate, 8.0% vs. 36.0%, P<0.001). Multivariate Cox analysis showed that low CCR (HR=2.395, 95% CI: 1.234-4.648, P=0.010 for PFS rate; HR=2.528, 95% CI: 1.317-4.854, P=0.005 for OS rate) and low SATI (HR=2.188, 95% CI: 1.050-4.560, P=0.037 for PFS rate; HR=2.818, 95% CI: 1.381-5.752, P=0.004 for OS rate) were both independent prognostic factors of poor 8-month PFS rate and 16-month OS rate. A nomogram based on CCR and BC-parameters showed a good performance in predicting the 12- and 16-month OS, with a concordance index of 0.756 (95% CI, 0.722-0.789). Conclusions: Low pre-treatment CCR and SATI were independently associated with lower response rates and worse survival in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy.

Efficacy and safety of acupuncture for postpartum hypogalactia: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Postpartum hypogalactia (PH) is prominent during lactation and may negatively impact the mother's or infant's health. Acupuncture is widely used to increase maternal breast milk production. However, the effects of acupuncture on PH remain unclear. Therefore, this review aimed to evaluate the efficacy and safety of acupuncture in individuals with PH. MATERIALS AND METHODS: Articles on potentially eligible randomized controlled trials (RCTs) on acupuncture for PH published from database inception to October 2023 were retrieved from the PubMed, Web of Science, Cochrane Library, EMBASE, EBSCO, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, WanFang, and VIP databases. Two reviewers independently screened the records, extracted essential information, and evaluated the methodological quality of the RCTs using the revised Cochrane risk-of-bias (RoB) tool. The primary outcome was a change in serum prolactin (PRL) levels before and after treatment. Secondary outcomes included milk secretion volume (MSV), total effective rate (TER), mammary fullness degree (MFD), and exclusive breastfeeding rate (EBR). Meta-analyses were performed using RevMan v5.4. Finally, the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. RESULTS: This study included 19 RCTs involving 2,400 participants. The included studies were classified as having an unclear to high RoB. Our findings indicated that, overall, acupuncture showed a significant effect in increasing serum PRL levels (standardized mean differences [SMDs] = 1.09, 95% confidence interval [CI]: 0.50, 1.68), MSV (SMD = 1.69, 95% CI: 0.53, 2.86), TER (relative risk [RR] = 1.25, 95% CI: 1.10, 1.42), and EBR (RR = 2.01, 95% CI: 1.07, 3.78) compared to that in the control group; however, no difference in MFD (SMD = 1.17, 95% CI: -0.09, 2.42) was observed. In the subgroup analysis, acupuncture combined with Chinese herbs or conventional treatment was significantly more effective in increasing serum PRL levels, MSV, and TER than did Chinese herbs or conventional treatment alone. Moreover, acupuncture alone resulted in significantly higher serum PRL levels compared to Chinese herbs; however, this benefit was not observed for TER and MFD. The quality of evidence was critically low. CONCLUSION: Acupuncture may effectively increase milk secretion in women with PH. However, owing to the low quality of evidence, further rigorously designed studies are warranted to confirm our findings.

[Chiral capillary gas chromatography for the separation of the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane].

Chiral compounds play an important role in the pharmaceutical industry owing to their unique biological activities. The enantiomers must be separated because they can exhibit different pharmacological activities. Thus, the development of chiral separation methods is essential to determine the purity of enantiomers. 4-Chloromethyl-2,2-dimethyl-1,3-dioxolane is an important chiral pharmaceutical intermediate. In this context, a method based on chiral capillary gas chromatography was established for the separation and determination of the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane. The separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane was initially investigated using two conventional stationary-phase capillary columns: SH-I-5Sil MS and SH-WAX. The stationary phase of SH-I-5Sil MS consisted of 5% phenyl and 95% polymethylsiloxane, whereas the stationary phase of SH-WAX consisted of 100% crosslinked polyethylene glycol. Neither of the columns exhibited chiral selectivity, so they both were unable to separate the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane. Subsequently, the separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane was investigated using four chiral columns: Rt-bDEXm, Rt-bDEXsm, Rt-bDEXse, and InertCap CHIRAMIX. Among the chiral columns, Rt-bDEXse, which used a stationary phase composed of 2,3-di-O-ethyl-6-O-tert-butyl dimethylsilyl ß-cyclodextrin added to 14% cyanopropyl phenyl and 86% dimethyl polysiloxane, achieved the best separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane. Thus, this column was selected as the analytical column for further method optimization. Detection was performed using a hydrogen flame ionization detector. The effects of various gas chromatographic parameters, such as linear velocity, initial column temperature, column heating rate, and solvent type, on the separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane were investigated. The optimal chromatographic conditions included a linear velocity of 70 cm/s, an initial column temperature of 70 ℃, and a column heating rate of 2.0 ℃/min. The final column oven temperature was 150 ℃. Methanol, ethanol, ethyl acetate, n-hexane, dichloromethane, and dimethyl sulfoxide were selected as solvents. The results showed that dimethyl sulfoxide interfered with the peaks of the target compounds, whereas the other solvents had no significant effect on the peak shape and separation of (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane. Methanol was finally selected as the solvent in this study. Further experiments revealed that (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane could be rapidly separated within 10 min, with a resolution greater than 1.5. A good linear relationship was observed in the range of 0.5-50.0 mg/L, with a linear correlation coefficient greater than 0.998. The limits of detection for (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane were 0.07 and 0.08 mg/L, respectively, and the corresponding limits of quantification were 0.22 and 0.25 mg/L, respectively. Spiked recovery tests were performed at three spiked levels of 0.5, 2.0, and 10.0 mg/L using methanol as the blank to determine the accuracy of the proposed method. The recoveries for (R)- and (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane were 94.0%-99.1% and 96.0%-98.8%, respectively, with relative standard deviations (RSDs) of 1.26%-4.87% and 1.51%-4.46%, respectively. The established method is efficient and reliable; thus, it can serve as a reference for the separation of the enantiomers of 4-chloromethyl-2,2-dimethyl-1,3-dioxolane. It can also potentially be applied to evaluate the enantiomeric purity of other chiral compounds in the pharmaceutical industry and produce chiral drugs and other related compounds.

Chemotherapeutic and targeted drugs-induced immunogenic cell death in cancer models and antitumor therapy: An update review.

As traditional strategies for cancer treatment, some chemotherapy agents, such as doxorubicin, oxaliplatin, cyclophosphamide, bortezomib, and paclitaxel exert their anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells. ICD induces anti-tumor immunity through release of, or exposure to, damage-related molecular patterns (DAMPs), including high mobility group box 1 (HMGB1), calreticulin, adenosine triphosphate, and heat shock proteins. This leads to activation of tumor-specific immune responses, which can act in combination with the direct killing functions of chemotherapy drugs on cancer cells to further improve their curative effects. In this review, we highlight the molecular mechanisms underlying ICD, including those of several chemotherapeutic drugs in inducing DAMPs exposed during ICD to activate the immune system, as well as discussing the prospects for application and potential role of ICD in cancer immunotherapy, with the aim of providing valuable inspiration for future development of chemoimmunotherapy.

NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor.

Tumorigenesis and tumor development are closely related to the abnormal regulation of ubiquitination. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin ligase critical to the ubiquitination process, plays key roles in the regulation of cancer stem cells, as well as tumor cell functions, including cell proliferation, apoptosis, cell cycle regulation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor drug resistance, by controlling subsequent protein degradation through ubiquitination. NEDD4L primarily functions as a tumor suppressor in several tumors but also plays an oncogenic role in certain tumors. In this review, we comprehensively summarize the relevant signaling pathways of NEDD4L in tumors, the regulatory mechanisms of its upstream regulatory molecules and downstream substrates, and the resulting functional alterations. Overall, therapeutic strategies targeting NEDD4L to treat cancer may be feasible.

Efficacy and safety of acupuncture for postpartum hypogalactia: protocol for a systematic review and meta-analysis.

INTRODUCTION: Breast milk is recognised as the best natural food for neonates, but many women experience postpartum hypogalactia (PH). Randomised trials have found that acupuncture exert therapeutic effect on women with PH. However, systematic reviews on the efficacy and safety of acupuncture are still lacking; therefore, this systematic review aims to evaluate the efficacy and safety of acupuncture for PH. METHODS AND ANALYSIS: Six English databases (PubMed, Cochrane Library, EMBASE, EBSCO, Scopus, and Web of Science) and four Chinese databases (China National Knowledge Infrastructure, Wan-Fang, Chinese Biomedical Literature and Chinese Scientific Journal) will be systematically searched from their establishment to 1 September 2022. Randomised controlled trials of the efficacy of acupuncture for PH will be reviewed. The study selection, data extraction and research quality evaluation will be conducted independently by two reviewers. The primary outcome is the change in serum prolactin level from baseline to the end of treatment. Secondary results include milk secretion volume, total effectiveness rate, degree of mammary fullness, rate of exclusive breast feeding, and adverse events. A meta-analysis will be performed using RevMan V.5.4 statistical software. Otherwise, a descriptive analysis will be conducted. The risk of bias will be assessed using the revised Cochrane risk-of-bias tool. ETHICS AND DISSEMINATION: This systematic review protocol does not require ethical approval because it does not include private information/data of the participants. This article will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42022351849.

Efficacy and safety of weekly versus triweekly cisplatin treatment concomitant with radiotherapy for locally advanced nasopharyngeal carcinoma: A systematic review and pooled analysis.

Background: Most nasopharyngeal carcinoma cases are diagnosed at an advanced stage due to their hidden anatomical structure and atypical clinical symptoms and often require chemoradiotherapy. Here, we present a systematic review and pooled analysis to synthesize existing research on the efficacy and adverse effects of weekly versus triweekly cisplatin chemotherapy concomitant with radiotherapy for locally advanced nasopharyngeal carcinoma (LANPC). Methods: We searched the PubMed, Embase, and Cochrane Library databases from inception to 1 September 2021, for relevant original research articles published in English. The literature search and data extraction were done independently by two investigators. We used random-effects models to provide point estimates [95% confidence interval (CI)] of overall response rate (ORR), overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and the incidence rate of adverse effects (AEs) and with subgroup analysis according to each study type. The primary endpoints were ORR, OS, and PFS; LRFS, DMFS, and grade ≥3 acute AEs were secondary endpoints. Results: In total, 2,305 patients of eight studies were included in this review. We found that patients who were administered cisplatin weekly or triweekly had no differences in ORR, OS, PFS, DMFS, LRFS, severe mucositis, dermatitis, nausea/vomiting or nephrotoxicity. Patients who were administered weekly cisplatin were at a higher risk of hematological toxicity compared with patients who received the chemotherapy triweekly. Conclusion: Our findings suggest that both regimens could be recommended as the standard of care for the chemoradiotherapy treatment of LANPC, the perceived benefit of lower toxicity with weekly cisplatin could not be established.