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The relationships between the exposure to ambient air pollutants during gestation and the incidence of hypertensive disorders in pregnancy (HDPs) or preeclampsia are contradictory. This prospective cohort study enrolled the participants between January 2020 and December 2021 from the Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology. The exposure to ambient air pollutants and daily temperatures were obtained from the ChinaHighAirPollutants dataset and the Big Earth Data Platform for Three Poles, respectively. Logistic regression models were used as single- and two-pollutant models. Restricted cubic splines were applied to each ambient air pollutant exposure to further evaluate the exposure-response relationships. Quantile G-computation approaches were employed to evaluate the cumulative impact of mixed ambient air pollutants on the incidence risk HDPs and preeclampsia. Among 19,325 participants (median age: 30.2 years), 1669 (8.64%) were diagnosed with HDPs and 180 (0.94%) with preeclampsia. While mostly null risk estimates were observed, exposure to PM1, PM2.5, PM10, and NO2 correlated with a decreased incidence risk for HDPs and preeclampsia during most gestational periods. Additionally, our multi-pollutant model presented that an increase by one quartile in the cumulative effect of ambient air pollutants was associated with a significantly decreased incidence risk for HDPs in the trimester before gestation and in the third trimester during gestation, as well as for preeclampsia in the third trimester during gestation. These findings warrant further investigation into the mechanisms underlying these associations.
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Non-coding RNAs are mainly divided into two categories, one is small non-coding RNA represented by miRNA, and the other is long non-coding RNA longer than 200 bp. Further studies on non-coding RNAs have revealed that long non-coding RNAs not only have carcinogenic effects, but also have potential links with miRNAs. Antisense non-coding RNA in the INK4 locus (ANRIL/CDKN2B-AS1), one of the five subtypes of long non-coding RNA, has been proved to play a role of oncogene in many cancers, such as gastric cancer, cervical cancer, prostate cancer and non-small cell lung cancer. Knockdown ANRIL can significantly inhibit the proliferation and migration of cancer cells, while also negatively regulating the expression of related miRNAs. This suggests that ANRIL may serve as a potential target for the development of drugs that provide new strategies to improve the effectiveness of cancer treatment. In our review, we summarize the current association between ANRIL and miRNAs in various cancers.
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Among all cancers in the world, the incidence rate of digestive system neoplasms accounts for about 25%, while the mortality rate accounts for about 35%. Difficulty in detecting early digestive system cancers and its poor prognosis are the two main reasons for the high mortality rate. Understanding of the basic cellular processes is of significance and autophagy is one of these processes. Considering the importance of autophagy in pathological state functions, the mechanism of autophagy was initially carried out. In this paper, we will review the molecular mechanisms and biological functions of autophagy-associated ncRNAs in different types of digestive system cancers. Autophagy is a process that supports nutrient cycling and metabolic adaptation accomplished through multi-step lysosomal degradation. It has been suggested that autophagy has a dual role in cancer, which limits tumorigenesis in some stages but promotes tumor progression in others. NcRNAs are also shown to modulate cellular autophagy and thus affect the development of digestive system neoplasms. More and more evidence suggests that the regulation of autophagy by ncRNAs plays a complex role in cancer initiation, progression, metastasis, recurrence, and treatment resistance, which might make ncRNAs therapeutic targets for digestive system neoplasms. While miRNAs participate mainly in post-transcriptional regulation, lncRNAs, and circRNAs usually serve as molecular sponges that have more diverse regulatory functions.
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As lncRNAs have increasingly been investigated, they are no longer simply defined as RNAs with no transcription capability. Studies have identified significant associations between the abnormal expression of lncRNAs and human diseases, particularly the mechanisms by which lncRNAs play a part in cancers, which are of considerable attention to researchers. As a result of the complex spatial structure, the mechanisms of interaction of lncRNAs in cancer cells are also complicated and diversified. Among a series of lncRNAs, TUG1, which is now considered to be a very high-value lncRNA, has recently been identified to express abnormally in some malignancies, leading to different alterations in cancer cells proliferation, migration, invasion, apoptosis, and drug resistance, and hence promoting or inhibiting cancer progression. Current studies have implicitly indicated that TUG1 can be used as a therapeutic target for human cancers. However, the biological functions of TUG1 have been studied for a short period of time, and the complete molecular mechanism still needs to be clarified. Accordingly, this review focuses on the principal molecular mechanisms of TUG1 in human cancers and the specific mechanisms of action in different cancer development processes based on existing studies.
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CircRNA is stable due to its ring structure and is abundant in humans, which not only exists in various tissues and biofluids steadily but also plays a significant role in the physiology and pathology of human beings. CircPVT1, an endogenous circRNA, has recently been identified from the PVT1 gene located in the cancer risk region 8q24. CircPVT1 is reported to be highly expressed in many different tumors, where it affects tumor cell proliferation, apoptosis, invasion, and migration. We summarize the biosynthesis and biological functions of circPVT1 and analyze the relationship between circPVT1 and tumors as well as its significance to tumors. Further, it's noteworthy for the diagnosis, treatment, and prognosis of cancer patients. Therefore, circPVT1 is likely to become an innovative tumor marker.
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MiRNAs are confirmed to be a kind of short and eminently conserved noncoding RNAs, which regulate gene expression at the post-transcriptional level via binding to the 3'- untranslated region (3'-UTR) of targeting multiple target messenger RNAs. Recently, growing evidence stresses the point that they play a crucial role in a variety of pathological processes, including human cancers. Dysregulated miRNAs act as oncogenes or tumor suppressor genes in many cancer types. Among them, we noticed that miR-122 has been widely reported to significantly influence carcinogenicity in a variety of tumors by regulating target genes and signaling pathways. Here, we focused on the expression of miR-122 in regulatory mechanisms and tumor biological processes. We also discussed the effects of miR-122 dysregulation in various types of human malignancies and the potential to develop new molecular miR-122-targeted therapies. The present review suggests that miR-122 may be a potentially useful cancer diagnosis and treatment biomarker. More clinical diagnoses need to be further launched in the future. A promising direction to improve the outcomes for cancer patients will likely combine miR-122 with other traditional tumor biomarkers.
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MicroARNs , Neoplasias , MicroARNs/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Animales , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
Licorice from Glycyrrhiza uralensis roots is used in foods and medicines. Although we are aware that licorice roots and leaves have distinct material compositions, the specific reasons for these differences remain unknown. Comparison of the metabolomes and transcriptomes between the leaves and roots revealed flavonoids and triterpenoid saponins were significantly different. Isoflavones were enriched in roots because of upregulation of genes encoding chalcone isomerase and flavone synthase, which are involved in isoflavone synthesis. Six triterpenoid saponins were significantly enriched only in the roots. The leaves did not accumulate glycyrrhetinic acid because of low expression levels of genes involved in its synthesis. A gene encoding a UDP glycosyltransferase, which likely catalyzes the key step in the transformation of glycyrrhetinic acid to glycyrrhizin, was screened. Our results provide information about the differences in flavonoid and triterpenoid synthesis between roots and leaves, and highlight targets for genetic engineering. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01467-y.
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BACKGROUND: Hyperuricemia is prevalent in individuals with chronic kidney disease (CKD). Elevated serum uric acid (SUA) concentrations have been considered an independent risk factor for the onset of CKD. However, the relationship between SUA concentrations and long-term health outcomes among patients with CKD remains unclear. METHODS: We performed a prospective cohort study with nationally representative sample to investigate the relationship between SUA concentrations and mortality risk including all-cause, cardiovascular disease (CVD) and cancer mortality, among patients with CKD. The weighted restricted cubic spline analyses combined with the multivariate-adjusted Cox proportional hazard models were used to test the nonlinearity of relationship. RESULTS: The 6642 patients participating in National Health and Nutrition Examination Survey 1999-2018 were enrolled. During 656 885 person-months of follow-up time, 2619 all-cause deaths were recorded, including 1030 CVD deaths and 458 cancer deaths. Our study presented J-shaped non-linear relationships between SUA concentrations and all-cause and CVD mortality with inflection points at 311.65 µmol/L and 392.34 µmol/L, respectively. When SUA concentration was higher than those inflection points, every increase of 50 µmol/L SUA was associated with 11.7% and 17.0% greater multivariable-adjusted hazard ratio of all-cause and CVD mortality, respectively. In addition, a negative linear correlation with cancer mortality was detected. CONCLUSION: These findings suggested that maintaining appropriate SUA concentrations may improve long-term health outcomes among CKD patients. The corresponding inflection points of J-shaped non-linear relationships were 311.65 and 392.34 µmol/L for all-cause and CVD mortality. Further clinical trials are required to investigate uric acid-lowering targets.
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Enfermedades Cardiovasculares , Neoplasias , Insuficiencia Renal Crónica , Humanos , Ácido Úrico , Estudios Prospectivos , Encuestas Nutricionales , Factores de Riesgo , Enfermedades Cardiovasculares/diagnóstico , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND: International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA). METHODS: We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines. RESULTS: Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA = 78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA = 94.1%), abemaciclib+NSAI (SUCRA = 69.9%), and ribociclib+NSAI (SUCRA = 68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision. CONCLUSIONS: Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).
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Aminopiridinas , Bencimidazoles , Neoplasias de la Mama , Inhibidores de Proteínas Quinasas , Purinas , Humanos , Femenino , Fulvestrant/uso terapéutico , Metaanálisis en Red , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/uso terapéuticoRESUMEN
Lung cancer remains one of the most common malignant cancers worldwide, and its survival rate is extremely low. Chemotherapy, the mainstay of lung cancer treatment, is not as effective as it could be due to the development of cellular resistance. The molecular mechanisms of drug resistance in lung cancer remain to be elucidated. Accumulating evidence suggests that ceRNAs are involved in various carcinogenesis and development. CeRNA is a transcript that regulates each other through competition with miRNA. However, the relationship between ceRNAs and chemoresistance in lung cancer remains unclear. In this narrative review, we provided a summary of treatment approaches that focus on ceRNA networks to overcome drug resistance.
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Introduction: Researchers have investigated the causal effect between serum uric acid (SUA) concentrations and kidney function for decades, but studies produced inconsistent results. This study aimed to clarify the bidirectional causal effects between SUA concentrations and kidney function and to explore the potential ethnic disparities by conducting a trans-ethnic Mendelian randomization study in European, African, and Asian ancestries. Materials and methods: The summary-level data for this study were obtained from the Global Urate Genetics Consortium, CKDGen Consortium, UK Biobank, and Japan Biobank for different outcomes and exposures, respectively. The traits of kidney function were estimated glomerular filtration rate from serum creatinine (eGFRcr), estimated glomerular filtration rate from cystatin C (eGFRcys), and blood urea nitrogen (BUN). Using the multiplicative random-effects inverse variance weighting mode, our primary analysis produced robust results despite heterogeneity. Additionally, we performed the Mendelian randomization pleiotropy residual sum and outlier test to eliminate the horizontal pleiotropy and obtain accurate results. Results: Our findings revealed that elevated SUA concentrations had causal effects on declined eGFRcys, BUN, and a diagnosis of chronic kidney disease in European ancestries and eGFRcr in Asian ancestries. Additionally, the causal effects of declined eGFRcr and elevated BUN concentrations on elevated SUA concentrations were observed in both European and Asian ancestries. However, no bidirectional causal effect was found between SUA concentrations and eGFRcr among African ancestries. Conclusions: This trans-ethnic Mendelian randomization study confirmed the bidirectional causal effects between SUA concentrations and kidney function and highlighted the importance of considering ethnic disparities in clinical treatments.
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Background: Peripheral blood inflammation indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have become research hotspots in the diagnosis, treatment, and prognosis prediction of breast cancer, whereas existing research findings remain controversial. Methods: Data pertaining to 1808 breast cancer patients were collected retrospectively to analyze the predictive value of NLR/PLR/SII for breast cancer clinicopathological characteristics, chemotherapy response, and relapse. 1489, 258, and 53 eligible breast cancer patients entered into the three analyses, respectively. Logistic regression analyses were used to assess the correlation between these indices and poor response to chemotherapy. A predictive scoring model was established to predict chemotherapeutic responses based upon the odds ratio values of significant variables identified in logistic regression analyses. Results: Higher pretherapeutic NLR/PLR/SII values were significantly correlated with higher tumor stage, triple-negative breast cancer, premenopausal status, and younger age. Logistic regression analyses indicated that pretherapeutic high SII (as a continuous variable or with a cut-off value of 586.40) and HER2-negative status were independent predictors of poor response to neoadjuvant chemotherapy. A first-in-class SII-based predictive scoring model well distinguished patients who might not benefit from neoadjuvant chemotherapy, with an area under the curve of 0.751. In HR-positive cancers, SII was more strongly associated with clinicopathological features and chemotherapy response. In addition, a receiver operating characteristic curve analysis indicated that the specificity of follow-up SII in identifying cancer relapse was greater than 98.0% at a cut-off value of 900. Conclusion: As a predictor of breast cancer, especially in the HR-positive subtype, SII may eclipse NLR/PLR. SII-high patients are more likely to have a worse chemotherapy response and a higher risk of recurrence.
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Background: As for the coronary artery inflammation and coronary atherosclerotic burden, which are used to assess the risk of adverse cardiac events in patients, it is unclear whether there is any certain correlation between them. Therefore, the purpose of this study was to explore the potential relationship between coronary artery inflammation and coronary atherosclerotic burden. Methods: A total of 346 eligible patients underwent assessment of computed tomography (CT) attenuation values of pericoronary adipose tissue (PCAT) in the right coronary artery and Agatston coronary artery calcium (CAC) based on coronary CT angiography. These measurements were utilized to evaluate coronary inflammation and atherosclerotic burden, respectively. Patients with a CAC score of 0 were categorized into groups based on the presence or absence of coronary artery disease (CAD). CAC scores of 10, 100, and 400 were chosen as cutoff values to compare differences in PCAT attenuation values across different CAC scores. Results: When comparing all CAD patients to non-CAD patients, a significantly higher PCAT attenuation was observed in CAD patients (-87.54±9.39 vs. -93.45±7.42 HU, P=0.000). The PCAT attenuation in CAD patients with a CAC score of 0 was significantly higher than that in patients with a CAC score greater than 0 and in non-CAD patients with a CAC score of 0 (-82.63±8.70 vs. -90.38±8.59 vs. -93.45±7.42 HU, P=0.000). The PCAT attenuation values did not exhibit significant differences among different CAC scores (all P>0.05); however, it was highest in CAD patients with a CAC score of 0 (P<0.05). Body mass index, hyperlipidemia, hypertension, and PCAT attenuation were identified as independent risk factors in both CAD patients with a CAC score of 0 and patients with a CAC score greater than 0 (all P<0.05). Conclusions: The results of this study suggest that a direct relationship between coronary inflammation and coronary atherosclerotic burden is not evident. Nonetheless, it is noteworthy that coronary inflammation was most pronounced in CAD patients with a CAC score of 0, while CAC score did not demonstrate an association with inflammation.
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Objective: Random skin flaps have many applications in plastic and reconstructive surgeries. However, distal flap necrosis restricts wider clinical utility. Mitophagy, a vital form of autophagy for damaged mitochondria, is excessively activated in flap ischemia/reperfusion (I/R) injury, thus inducing cell death. Aldehyde dehydrogenase-2 (ALDH2), an allosteric tetrameric enzyme, plays an important role in regulating mitophagy. We explored whether ALDH2 activated by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) could reduce the risk of ischemic random skin flap necrosis, and the possible mechanism of action. Methods: Modified McFarlane flap models were established in 36 male Sprague-Dawley rats assigned randomly to three groups: a low-dose Alda-1 group (10 mg/kg/day), a high-dose Alda-1 group (20 mg/kg/day) and a control group. The percentage surviving skin flap area, neutrophil density and microvessel density (MVD) were evaluated on day 7. Oxidative stress was quantitated by measuring the superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Blood perfusion and skin flap angiogenesis were assessed via laser Doppler flow imaging and lead oxide-gelatin angiography, respectively. The expression levels of inflammatory cytokines (IL-1ß, IL-6, and TNF-α), vascular endothelial growth factor (VEGF), ALDH2, PTEN-induced kinase 1 (PINK1), and E3 ubiquitin ligase (Parkin) were immunohistochemically detected. Indicators of mitophagy such as Beclin-1, p62, and microtubule-associated protein light chain 3 (LC3) were evaluated by immunofluorescence. Results: Alda-1 significantly enhanced the survival area of random skin flaps. The SOD activity increased and the MDA level decreased, suggesting that Alda-1 reduced oxidative stress. ALDH2 was upregulated, and mitophagy-related proteins (PINK1, Parkin, Beclin-1, p62, and LC3) were downregulated, indicating that ALDH2 inhibited mitophagy through the PINK1/Parkin signaling pathway. Treatment with Alda-1 reduced neutrophil infiltration and expressions of inflammatory cytokines. Alda-1 significantly upregulated VEGF expression, increased the MVD, promoted angiogenesis, and enhanced blood perfusion. Conclusion: ALDH2 activation can effectively enhance random skin flap viability via inhibiting PINK1/Parkin-dependent mitophagy. Moreover, enhancement of ALDH2 activity also exerts anti-inflammatory and angiogenic properties.
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Daño por Reperfusión , Factor A de Crecimiento Endotelial Vascular , Animales , Masculino , Ratas , Aldehído Deshidrogenasa/uso terapéutico , Beclina-1 , Citocinas/uso terapéutico , Isquemia , Necrosis , Complicaciones Posoperatorias , Proteínas Quinasas/metabolismo , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Superóxido Dismutasa , Ubiquitina-Proteína Ligasas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Studies have found that RNA encoding proteins only account for a small part of the total number, most RNA is non-coding RNA, and non-coding RNA may affect the occurrence and development of human cancers by affecting gene expression, therefore play an important role in human pathology. At present, ncRNAs studied include miRNA, circRNA, lncRNA, piRNA, and snoRNA, etc. After decades of research, the basic role of these ncRNAs in many cancers has been clear. As far as we know, the role of miRNAs in cancer is one of the hottest research directions, however, it is also found that the imbalance of ncRNAs will affect the occurrence of gastric cancer, breast cancer, lung cancer, meanwhile, it may also affect the prognosis of these cancers. Therefore, the study of ncRNAs in cancers may help to find new cancer diagnostic and treatment methods. Here, we reviewed the biosynthesis and characteristics of miRNA, cricRNA, and lncRNA etc., their roles in human cancers, as well as the mechanism through which these ncRNAs affect human cancers.
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RATIONALE AND OBJECTIVES: We investigated the diagnostic performance of dual-energy CT (DECT) virtual non-calcium (VNCa) and Rho/Z images for bone marrow infiltration of primary malignant bone tumors (PMBTs). MATERIALS AND METHODS: We retrospectively analyzed 65 patients with PMBT who underwent DECT and MRI within 2 weeks. DECT was used to evaluate the presence and extent of marrow involvement surrounding PMBTs using the SCT, VNCa, and Rho/Z images. MRI was used as the reference standard for measurements. CT values of normal and involved bone marrow areas were measured on VNCa images, and Zeff values were measured on Rho/Z images. The statistical methods used were the 2*C chi-square test, ANOVA test, paired samples t test, and diagnostic performance of the different variables were evaluated using receiver operating characteristic curves. RESULTS: VNCa and Rho/Z images showed higher accuracy (91%, 92% vs. 67%) and sensitivity (90%, 92% vs. 69%) than SCT images for diagnosing bone marrow infiltration in patients with PMBT. The maximum longitudinal diameter of tumor involvement measurements was statistically different between VNCa and SCT, Rho/Z and SCT, MRI, and SCT (all p < 0.05, p = 0.047, p = 0.049, and p = 0.023, respectively). The maximum transverse diameter was statistically significant between SCT and MRI, VNCa and MRI, Rho/Z and MRI (all p < 0.05, and p = 0.015, and p = 0.044, and p = 0.047, respectively). The HU or Zeff values based on the area of interest of VNCa and Rho/Z images differed significantly between the normal and infiltrated bone marrow area (p < 0.001). Receiver operating characteristic curve analysis revealed area under the curves of 0.995 and 0.988, respectively, with cut-off values of -31.57 HU and 7.8, and the sensitivity of both was 96.9%. CONCLUSION: DECT-VNCa and Rho/Z images have good diagnostic value when evaluating bone marrow infiltration in PMBTs.
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Médula Ósea , Neoplasias Óseas , Humanos , Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Calcio , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Imagen por Resonancia Magnética/métodos , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/patología , Sensibilidad y Especificidad , EdemaRESUMEN
The development of potassium-ion batteries (PIBs) has been impeded by the lack of an appropriate carbon anode material that could accommodate K+ with a large ionic radius. Hard carbon with low cost and larger interlayer spacing is a promising anode material for PIBs. However, the impact of oxygen-containing functional groups in hard carbon (HC) is less reported. Herein, a hypercrosslinked polymer (HCLP) is prepared and used for the synthesis of microporous hard carbons with superior structural stability and abundant oxygen-containing functional groups and defects, in which the crosslinking agent provided copious oxygen atoms. It is found that a large number of CâO groups and micropores provide more storage sites for K+. The surface-controlled process is dominated by the reversible reaction of CâO + K+ + e- â C-O-K, which directly increases the capacity contribution. The HCs obtained at 600 °C exhibit good cycling and rate performance with an initial specific capacity of about 254.3 mAh g-1 and the capacity retention of 83.2% after 200 cycles at 50 mA g-1. The capacity reached up to 121 mAh g-1 at 2 A g-1. A possible capacitive-adsorption mechanism is proposed by kinetic analysis. The redox reaction mechanism between CâO and K+ at the HC is clearly also revealed.
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Objective: Programmed cell death 1 (PD-1) inhibitor has been in the market in China for several years, which lacks sufficient domestic evidence regarding its application in lung cancer. Thus, this study intended to assess the treatment outcome and tolerance of PD-1 inhibitor plus chemotherapy in advanced, driver-gene-negative, nonsquamous, non-small-cell lung cancer (NSCLC) patients in a real clinical setting. Methods: This retrospective cohort study analyzed 68 advanced driver-gene-negative nonsquamous NSCLC patients, among which 38 cases received PD-1 inhibitor plus chemotherapy and 30 cases adopted chemotherapy alone. Disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were reviewed. Results: Generally, PD-1 inhibitor plus chemotherapy achieved a more satisfying ORR compared with chemotherapy alone (52.6% vs. 30.0%, P = 0.061), while the DCR did not vary between PD-1 inhibitor plus chemotherapy and chemotherapy (84.2% vs. 73.3%, P = 0.271). Patients receiving PD-1 inhibitor plus chemotherapy exhibited favorable PFS (median: 10.1 vs. 7.1 months, P = 0.040) and OS (median: 17.4 vs. 13.9 months, P = 0.049) than patients adopting chemotherapy alone. Additionally, after adjustment using multivariable Cox's analyses, PD-1 inhibitor plus chemotherapy (vs. chemotherapy) could independently realize prolonged PFS (P = 0.020) and OS (P = 0.029). Moreover, the majority of adverse events were manageable; meanwhile, grade 3-4 adverse events included leukopenia (13.2%), neutropenia (13.2%), nausea and vomiting (7.9%), anemia (5.3%), elevated transaminase (5.3%), thrombopenia (2.6%), anorexia (2.6%), peripheral neuropathy (2.6%), and rash (2.6%). Conclusion: PD-1 inhibitor plus chemotherapy exhibits a better efficacy and equal tolerance compared with chemotherapy alone in advanced driver-gene-negative nonsquamous NSCLC patients.
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Germline PALB2 pathogenic variants are associated with an increased lifetime risk for breast, pancreatic, and ovarian cancer. However, the interpretation of the pathogenicity of numerous PALB2 missense variants of uncertain significance (VUSs) identified in germline genetic testing remains a challenge. Here we selected ten potentially pathogenic PALB2 VUSs identified in 2279 Chinese patients with breast cancer and evaluated their impacts on PALB2 function by systematic functional assays. We showed that three PALB2 VUSs p.K16M [c.47 A > T], p.L24F [c.72 G > C], and p.L35F [c.103 C > T] in the coiled-coil domain impaired PALB2-mediated homologous recombination. The p.L24F and p.L35F variants partially disrupted BRCA1-PALB2 interactions, reduced RAD51 foci formation in response to DNA damage, abrogated ionizing radiation-induced G2/M checkpoint maintenance, and conferred increased sensitivity to olaparib and cisplatin. The p.K16M variant presented mild effects on BRCA1-PALB2 interactions and RAD51 foci formation. Altogether, we identify two novel PALB2 VUSs, p.L24F and p.L35F, that compromise PALB2 function and may increase cancer risk. These two variants display marked olaparib and cisplatin sensitivity and may help predict response to targeted therapy in the clinical treatment of patients with these variants.
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INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) have had clinical success in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Notably, CDK4/6i have expanded to the neoadjuvant setting for early breast cancer and other cancer types and potently synergize with immunotherapy. Other CDKs, including CDK7, CDK9, and CDK12/13, mainly function in transcriptional processes as well as cell cycle regulation, RNA splicing, and DNA damage response. Inhibiting these CDKs aids in suppressing tumors, reversing drug resistance, increasing drug sensitivity, and enhancing anti-tumor immunity in breast cancer. AREAS COVERED: We reviewed the applications of CDK4/6i, CDK7i, CDK9i and CDK12/13i for various breast cancer subtypes and their potentials for combination with immunotherapy. A literature search of PubMed, Embase, and Web of Science was conducted in April 2022. EXPERT OPINION: The use of CDK4/6i represents a major milestone in breast cancer treatment. Moreover, transcription-related CDKs play critical roles in tumor development and are promising therapeutic targets for breast cancer. Some relevant clinical studies are underway. More specific and efficient CDKis will undoubtedly be developed and clinically tested. Characterization of their immune-priming effects will promote the development of combination therapies consisting of CDKi and immunotherapy.