Secondary cytoreductive surgery followed by olaparib tablets as maintenance therapy in patients with BRCA mutated recurrent ovarian cancer: A multi-center retrospective study.

OBJECTIVE: To evaluate the effect of secondary cytoreductive surgery (SeCRS) followed by platinum-based chemotherapy (PBC) and olaparib tablets as maintenance therapy in patients with BRCA mutated recurrent epithelial ovarian cancer. METHODS: This was a retrospective study of a prospective database. We collected information on 623 patients diagnosed with BRCA mutated recurrent epithelial ovarian cancer, all of whom underwent SeCRS followed by PBC in combination with or without olaparib. Overall survival and progression-free survival were measured to evaluate treatment effectiveness. RESULTS: Of the 623 patients recruited, 240 underwent SeCRS plus hyperthermic intraperitoneal chemotherapy followed by PBC and olaparib maintenance therapy (Group A), 248 underwent SeCRS followed by PBC and olaparib maintenance therapy (Group B), and 135 underwent SeCRS followed by PBC only upon recurrence (Group C). The median progression-free survival for Group A was significantly longer than that for Group B (32.5 vs. 24.2 months, P<0.001), and Group B was significantly longer than Group C (24.2 vs. 15.1 months, P<0.001). The median overall survival for Groups A was significantly longer than that for Group B (71.4 vs. 63.5 months, P<0.001), and Group B was significantly longer than Group C (63.5 vs. 47.5 months, P<0.001). CONCLUSIONS: This study suggested that SeCRS followed by PBC and olaparib maintenance therapy resulted in longer overall survival and progression-free survival than SeCRS followed by PBC only in patients with BRCA mutated recurrent ovarian cancer, especially in patients treated with SeCRS plus hyperthermic intraperitoneal chemotherapy.

PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis.

Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically, PAPAS transcription depends on R-loop formation at the 3' end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.

Highly Deformable High-Strength SiO2 Aerogel Designed with an Alternating Structure of Hard Cores and Flexible Chains for Thermal Insulation.

Thermally insulating aerogels can now be prepared from ceramics, polymers, carbon, and metals and composites between them. However, it is still a great challenge to make aerogels with high strength and excellent deformability. We propose a design concept of hard cores and flexible chains that alternately construct the aerogel skeleton structure. The approach gives the designed SiO2 aerogel excellent compressive (fracture strain 83.32%), tensile. and shear deformabilities, corresponding to maximum strengths of 22.15, 1.18, and 1.45 MPa, respectively. Also, the SiO2 aerogel can stably perform 100 load-unload cycles at a 70% large compression strain, demonstrating an excellent resilient compressibility. In addition, the low density of 0.226 g/cm3, the high porosity of 88.7%, and the average pore size of 45.36 nm effectively inhibit heat conduction and heat convection, giving the SiO2 aerogel outstanding thermal insulation properties [0.02845 W/(m·K) at 25 °C and 0.04895 W/(m·K) at 300 °C], and the large number of hydrophobic groups itself also gives it excellent hydrophobicity and hydrophobic stability (hydrophobic angle of 158.4° and saturated mass moisture absorption rate of about 0.327%). The successful practice of this concept has provided different insights into the preparation of high-strength aerogels with high deformability.

Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in the second-line treatment of advanced esophageal squamous cell carcinoma: a meta-analysis and systematic review.

Background: Esophageal cancer (EC) is the seventh most common cancer in the world, with 604,000 new cases diagnosed each year. Immune checkpoint inhibitors (ICIs) including programmed death ligand-1 (PD-L1) inhibitors have demonstrated a considerable survival advantage over chemotherapy in numerous randomized controlled trials (RCTs), particularly in patients with advanced esophageal squamous cell carcinoma (ESCC). In this analysis, we aimed to demonstrate that ICIs are more safe and effective than chemotherapy when used as a second-line treatment for advanced ESCC. Methods: Publications on the safety and efficiency of ICIs in advanced ESCC that were available prior to February 2022 were searched in the Cochrane Library, Embase, and PubMed databases. Studies with missing data were eliminated, and studies that compared the treatments between the immunotherapy group and chemotherapy group were included. Statistical analysis was carried out using RevMan 5.3, and risk and quality were evaluated with relevant evaluation tools. Results: Five studies met the inclusion criteria were selected, involving 1,970 patients with advanced ESCC. We compared chemotherapy and immunotherapy in the second-line treatment of advanced ESCC. ICIs considerably enhanced both the objective response rate (P=0.007) and overall survival (OS; P=0.001). However, the effect of ICIs on progression-free survival (PFS) was not significant (P=0.43). ICIs presented fewer grade 3-5 treatment-related adverse events (TRAEs), and there was also a suggested linkage between both PD-L1 expression and the effectiveness of the therapeutic intervention. Conclusions: For patients with advanced ESCC, ICIs are more effective and safer than chemotherapy, and thus have a higher treatment value.

Survival Outcomes of Sublobectomy and Lobectomy in Elderly Patients with Peripheral Solid-Dominant Non-small Cell Lung Cancer.

BACKGROUND: According to the JCOG0802 study, there were many non-cancer-related deaths in the lobectomy group. Meanwhile, the median age of the enrolled patients in the JCOG0802 study was 67 years old. Whether this difference in perioperative outcomes and survival outcomes is related to age remains unknown. We aim to investigate whether the sublobectomy was comparable to lobectomy in elderly (≥ 75 years old) patients with peripheral solid-dominant [50% ≤ consolidation tumor ratio (CTR) ≤ 1] and diameter ≤ 2 cm non-small cell lung cancer (NSCLC). METHODS: We retrospectively included 10,830 patients who underwent surgery treatment at two large-volume medical centers, Taizhou Hospital of Zhejiang Province and Shanghai Chest Hospital, from January 2016 to January 2018. Of these, 164 patients aged ≥ 75 years, tumor ≤ 2 cm, and 50% ≤ CTR ≤ 1 who received lobectomy or sublobectomy were included in our study. The perioperative outcomes, survival analyses, analysis of death patterns, tumor recurrence patterns, and Cox regression analyses were performed. RESULTS: On perioperative outcomes, sublobectomy was associated with a shorter operation time (p < 0.001), and in terms of survival outcomes, the 5-year overall survival (OS, p = 0.85) and 5-year disease-free surivial (DFS, p = 0.58) did not differ significantly between the two groups. The Cox regression analyses showed that CTR value, visceral pleural infiltration, and smoking were independent risk factors for worse OS. Furthermore, tumor recurrence pattern and death patterns between the two groups did not differ significantly. CONCLUSIONS: Sublobectomy could achieve superior perioperative outcomes and equivalent oncological efficacy in comparison with lobectomy in elderly patients (≥ 75 years old) with peripheral solid-dominant and diameter ≤ 2 cm NSCLC.

Comparative study on antimicrobial activity of mono-rhamnolipid and di-rhamnolipid and exploration of cost-effective antimicrobial agents for agricultural applications.

BACKGROUND: Chemical pesticides have defects in crop diseases control, such as narrow antimicrobial spectrum, chemicals residue risk and harm to farmland ecosystem. Antimicrobial agents from microbial sources are highly interested in agriculture. Studies showed that rhamnolipid biosurfactants possessed certain antimicrobial activity. The structural differences in rhamnolipid inevitably affect their activities. But the antimicrobial effect of mono-rhamnolipid and di-rhamnolipid is unknown. Rhamnolipid with unique structure can be produced using specific microbial cell factory. RESULTS: Different types of rhamnolipid were produced from different Pseudomonas aeruginosa strains. Rha-C10-C10 and Rha-Rha-C10-C10 were the main homologues in the separated mono-rhamnolipid and di-rhamnolipid, respectively. Both mono-rhamnolipid and di-rhamnolipid exhibited certain antimicrobial activity against the tested microbial strains, especially the fungi and Gram-positive bacteria. But mono-rhamnolipid was superior to di-rhamnolipid, with inhibition zone diameters larger than 25 mm and inhibition rate higher than 90%. The IC50 values of mono-rhamnolipid were lower than 5 mg/L against the tested bacterium and fungus, whereas the IC50 values of di-rhamnolipid were ranged from 10 mg/L to 20 mg/L. Mono-rhamnolipid stimulated the tested strains to generate higher level of intracellular ROS. Mono-rhamnolipid exhibited better antimicrobial activity to the potential agricultural pathogens, such as Alternaria alternata, Pantoea agglomerans and Cladosporium sp. The mono-rhamnolipid crude extract of strain P. aeruginosa SGΔrhlC can replace the separated mono-rhamnolipid. After 50 times dilution, the fermentation broth of the mono-rhamnolipid producing strain SGΔrhlC exhibited equal antimicrobial effect to mono-rhamnolipid (200 mg/L). Prospects of mono-rhamnolipid were also discussed for antimicrobial applications in agriculture. CONCLUSIONS: This work discovered that mono-rhamnolipid was superior to di-rhamnolipid on antimicrobial activity for agricultural applications. Mono-rhamnolipid is an excellent candidate for agricultural biocontrol. The knockout strain P. aeruginosa SGΔrhlC is an excellent microbial cell factory for high producing mono-rhamnolipid. Its mono-rhamnolipid crude extract and its diluted fermentation broth are cost-effective antimicrobial agents. This work provided new insights to develop green and efficient antimicrobial agents for agricultural applications.

Lymph node micrometastasis in non-small cell lung cancer.

Lung cancer has some of the highest morbidity and mortality rates of all cancers, and an important risk factor for mortality in patients with lung cancer is tumor metastasis. Even if a tumor is completely removed at an early stage of the disease, quite a number of patients still have the risk of recurrence. With the advent of molecular diagnostic and therapeutics, more and more studies have found that a poor prognosis may be related to lymph node micrometastasis. However, clinicians still find that predicting the prognosis and choosing the type of surgery and postoperative adjuvant chemotherapy are still challenging. Thus, this article reviews the current research status of lymph node micrometastasis in non-small cell lung cancer, envision to provide some updates and insights in this area.

Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFßR2 signaling pathway.

BRCA1 deficient breast cancers are aggressive and chemoresistant due, in part, to their enrichment of cancer stem cells that can be generated from carcinoma cells by an epithelial-mesenchymal transition (EMT). We previously discovered that BRCA1 deficiency activates EMT in mammary tumorigenesis. How BRCA1 controls EMT and how to effectively target BRCA1-deficient cancers remain elusive. We analyzed murine and human tumors and identified a role for Tgfßr2 in governing the molecular aspects of EMT that occur with Brca1 loss. We utilized CRISPR to delete Tgfßr2 and specific inhibitors to block Tgfßr2 activity and followed up with the molecular analysis of assays for tumor growth and metastasis. We discovered that heterozygous germline deletion, or epithelia-specific deletion of Brca1 in mice, activates Tgfßr2 signaling pathways in mammary tumors. BRCA1 depletion promotes TGFß-mediated EMT activation in cancer cells. BRCA1 binds to the TGFßR2 locus to repress its transcription. Targeted deletion or pharmaceutical inhibition of Tgfßr2 in Brca1-deficient tumor cells reduces EMT and suppresses tumorigenesis and metastasis. BRCA1 and TGFßR2 expression levels are inversely related in human breast cancers. This study reveals for the first time that a targetable TGFßR signaling pathway is directly activated by BRCA1-deficiency in the induction of EMT in breast cancer progression.

Integrin α6 overexpression promotes lymphangiogenesis and lymphatic metastasis via activating the NF-κB signaling pathway in lung adenocarcinoma.

OBJECTIVE: It has been reported that tumor-associated lymphangiogenesis plays an important role in lymph node metastasis and contributes to the poor survival of lung adenocarcinoma (LUAD) patients. As yet, however, the molecular mechanism underlying LUAD-associated lymphangiogenesis has remained elusive. METHODS: Immunohistochemistry (IHC) was used to determine the expression of integrin subunit alpha 6 (ITGA6) and the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1) in clinicopathologically characterized LUAD specimens. The effect of ITGA6 overexpression on lymphangiogenesis and lymphatic metastasis was examined by tube formation, scratch wound-healing, and cell migration assays in vitro and a popliteal lymph node metastasis model in vivo. Mechanistically, overexpression of ITGA6 and activation of NF-κB signaling were examined by real-time PCR, ubiquitination and dual-luciferase reporter assays. Finally, high ITGA6 expression in LUAD tissue samples was related to copy number variation (CNV) using the TCGA database. RESULTS: We found that ITGA6 overexpression correlated with microlymphatic vessel density in LUAD specimens (p < 0.01). Importantly, by using a popliteal lymph node metastasis model, we found that ITGA6 upregulation significantly enhanced lymphangiogenesis and lymphatic metastasis in vivo (p < 0.05). In addition, we found that ITGA6 overexpression enhanced the capability of A549 and H1299 LUAD cells to induce tube formation and migration in human lymphatic endothelial cells (HLECs). Mechanistically, we found that ITGA6 sustained NF-κB activity via binding and promoting K63 polyubiquitination of TNF receptor-associated factor 2 (TRAF2). Finally, CNV analysis revealed ITGA6 amplification of 27.5% in the LUAD tissue samples in the TCGA database. CONCLUSIONS: Taken together, our results uncover a plausible role for ITGA6 in mediating lymphangiogenesis and lymphatic metastasis and may provide a basis for targeting ITGA6 to treat LUAD lymphatic metastasis.

Loss of function of GATA3 induces basal-like mammary tumors.

Purpose: GATA3 is a transcription factor essential for mammary luminal epithelial cell differentiation. Expression of GATA3 is absent or significantly reduced in basal-like breast cancers. Gata3 loss-of-function impairs cell proliferation, making it difficult to investigate the role of GATA3 deficiency in vivo. We previously demonstrated that CDK inhibitor p18INK4c (p18) is a downstream target of GATA3 and restrains mammary epithelial cell proliferation and tumorigenesis. Whether and how loss-of-function of GATA3 results in basal-like breast cancers remains elusive. Methods: We generated mutant mouse strains with heterozygous germline deletion of Gata3 in p18 deficient backgrounds and developed a Gata3 depleted mammary tumor model system to determine the role of Gata3 loss in controlling cell proliferation and aberrant differentiation in mammary tumor development and progression. Results: Haploid loss of Gata3 reduced mammary epithelial cell proliferation with induction of p18, impaired luminal differentiation, and promoted basal differentiation in mammary glands. p18 deficiency induced luminal type mammary tumors and rescued the proliferative defect caused by haploid loss of Gata3. Haploid loss of Gata3 accelerated p18 deficient mammary tumor development and changed the properties of these tumors, resulting in their malignant and luminal-to-basal transformation. Expression of Gata3 negatively correlated with basal differentiation markers in MMTV-PyMT mammary tumor cells. Depletion of Gata3 in luminal tumor cells also reduced cell proliferation with induction of p18 and promoted basal differentiation. We confirmed that expression of GATA3 and basal markers are inversely correlated in human basal-like breast cancers. Conclusions: This study provides the first genetic evidence demonstrating that loss-of-function of GATA3 directly induces basal-like breast cancer. Our finding suggests that basal-like breast cancer may also originate from luminal type cancer.

A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future.

OBJECTIVE: This review summarizes the current status of neoadjuvant therapy and discusses the choice of new clinical research endpoints for non-small cell lung cancer. BACKGROUND: Neoadjuvant chemotherapy is a recognized practice in patients with resectable and locally advanced lung cancer. With the introduction of molecular targeted drugs and immune checkpoint inhibitors (ICIs), the overall survival (OS) of patients with lung cancer has been significantly improved, and the original traditional clinical research endpoints are no longer suitable for existing clinical research. In order to accelerate the process of clinical trials and the development and approval of drugs, it is necessary to find suitable alternative indicators as the main indicators of clinical research. METHODS: Therefore, this article focuses on clinical trials using disease-free survival (DFS), progression free survival, and pathological evaluation indicators, pathologic complete response and major pathologic response, as surrogate endpoints. We search related literature through PubMed database and clinical trials through clinicaltrials.gov. CONCLUSIONS: Pathologic complete response and major pathologic response are recommended as surrogate endpoints in the era of neoadjuvant immunotherapy, and secondary endpoints are listed for the prediction of pathological results. In addition, the definitions of major pathological response (MPR) and PCR should be standardized, and a new pathological evaluation standard should be developed, which is applicable to all current treatment methods. KEYWORDS: Neoadjuvant therapy; resectable lung cancer; clinical research endpoint; pathological response.

The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer.

Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.

Multi-Omics Characterization and Origin Assessment of Bilateral Lung Adenoid Cystic Carcinoma: A Case Report.

BACKGROUND: Primary adenoid cystic carcinoma (ACC) of the lung, which arises from the bronchial gland and is rare, accounting for only 0.04-0.2% of all primary lung tumors. The genetic profiling of bilateral ACC of unknown primary site and application in postoperative decision-making are less reported. CASE PRESENTATION: A 57-year-old male with a smoking history of over 30 years and multiple nodules in both lungs was present to our department. After assessing the bilateral solid nodules in his Positron Emission Tomography-Computed Tomography (PET/CT) scan, malignant lesions at the left lower lung, right lower lung, and right middle lung are suspected. Sequential selective video-assisted thoracoscopic surgeries (VATS) were performed. A genetic alteration test of 425 cancer-related genes and global gene expression profile of the specimens revealed intrapulmonary metastasis existed. The patient was followed up for three years without recurrence and tissue mutations in liquid biopsy. CONCLUSION: We present a way of omics-based multiple pulmonary lesions origin assessment, facilitating post-operative differential diagnosis and treatment decision for difficult cases.

Human PXR-mediated transcriptional activation of CYP3A4 by 'Fuzi' extracts.

OBJECTIVE: This study focused on determining whether the 'Fuzi' (FZ) extracts from different extraction methods are related to pregnane X receptor (PXR) and cytochrome P450 3A4 (CYP3A4), and explore the mechanism. METHODS: FZ was extracted under various conditions, and the components were identified by Ultra Performance Liquid Chromatography/Quad Time of Flight Mass Spectrometry (UPLC/Q-TOF-MS). Annexin V-FITC and propidium iodide staining assays were used to measure the cell cytotoxicity of these extracts. Real-time PCR, western blot analysis and reporter gene assay were used to detect the expression changes of PXR and CYP3A4. RESULTS: FZ extracts were found to contain high levels of monoester-diterpene alkaloids (MDAs) and diester-diterpene alkaloids (DDAs). FZ extracts were cytotoxic. Interestingly, we found that FZ extracts and DDAs can induce the expressions of PXR and CYP3A4. And the MDAs can inhibit the expressions of PXR and CYP3A4. CONCLUSION: Different extracts of FZ can induce the expressions of PXR and CYP3A4 in different degrees. This may be related to the drug-drug interactions.

Influences of Realgar-Indigo naturalis, A Traditional Chinese Medicine Formula, on the Main CYP450 Activities in Rats Using a Cocktail Method.

The purpose of this work was to study the influences of Realgar-Indigo naturalis (RIF) and its principal element realgar on 4 main cytochrome P450 enzymes activities in rats. A simple and efficient cocktail method was developed to detect the four probe drugs simultaneously. In this study, Wistar rats were administered intragastric RIF and realgar for 14 days; mixed probe drugs were injected into rats by caudal vein. Through analyzing the pharmacokinetic parameter of mixed probe drugs in rats, we can calculate the CYPs activities. The results showed that RIF could inhibit CYP1A2 enzyme activity and induce CYP2C11 enzyme activity significantly. Interestingly, in realgar high dosage group, CYP3A1/2 enzyme activity was inhibited significantly, and different dosage of realgar manifested a good dose-dependent manner. The RIF results indicated that drug coadministrated with RIF may need to be paid attention in relation to drug-drug interactions (DDIs). Realgar, a toxic traditional Chinese medicine (TCM), does have curative effect on acute promyelocytic leukemia (APL). Its toxicity studies should be focused on. We found that, in realgar high dosage group, CYP3A1/2 enzymes activity was inhibited. This phenomenon may explain its potential toxicity mechanism.

Probing the reactivity of microhydrated α-nucleophile in the anionic gas-phase S(N)2 reaction.

To probe the kinetic performance of microsolvated α-nucleophile, the G2(+)M calculations were carried out for the gas-phase S(N)2 reactions of monohydrated and dihydrated α-oxy-nucleophiles XO(-)(H2O)(n = 1,2) (X = HO, CH3O, F, Cl, Br), and α-sulfur-nucleophile, HSS(-)(H2O)(n = 1,2), toward CH3Cl. We compared the reactivities of hydrated α-nucleophiles to those of hydrated normal nucleophiles. Our calculations show that the α-effect of monohydrated and dihydrated α-oxy-nucleophiles will become weaker than those of unhydrated ones if we apply a plot of activation barrier as a function of anion basicity. Whereas the enhanced reactivity of monohydrated and dihydrated ROO(-) (R = H, Me) could be observed if compared them with the specific normal nucleophiles, RO(-) (R = H, Me). This phenomena can not be seen in the comparisons of XO(-)(H2O)(n = 1,2) (X = F, Cl, Br) with ClC2H4O(-)(H2O)(n = 1,2), a normal nucleophile with similar gas basicity to XO(-)(H2O)(n = 1,2). These results have been carefully analyzed by natural bond orbital theory and activation strain model. Meanwhile, the relationships between activation barriers with reaction energies and the ionization energies of α-nucleophile are also discussed.

Concerted or stepwise mechanism? New insight into the water-mediated neutral hydrolysis of carbonyl sulfide.

The water-mediated neutral hydrolysis mechanism of carbonyl sulfide (OCS) has been re-examined using the hybrid supramolecule/continuum models with n = 2-8 explicit water cluster at the level of MP2(fc)(CPCM)/6-311++G(d,p)//MP2(fc)(CPCM)/6-31+G(d). Present calculations indicate that the potential energy surface in water solution is different from the one in the gas-phase, and only stepwise mechanism is observed in aqueous solution, i.e., monothiocarbonic acid (H2CO2S) is formed via monothiocarbonate (OCSOH(-), MTC) and its counterion, protonated water cluster, (H2O)nH3O(+). The predicted rate-determining step (RDS) barrier for the stepwise mechanism in water solution, about 90 kJ/mol, shows good agreement with the experimental values, 83.7-96.2 kJ/mol using six- or eight-water model including two cooperative water molecules. Moreover, two reaction pathways, the nucleophilic addition of water molecule across the C═O or the C═S bond of OCS are competitive.

The α-effect exhibited in gas-phase S(N)2@N and S(N)2@C reactions.

In order to explore the existence of α-effect in gas-phase S(N)2@N reactions, and to compare its similarity and difference with its counterpart in S(N)2@C reactions, we have carried out a theoretical study on the reactivity of six α-oxy-Nus (FO(-), ClO(-), BrO(-), HOO(-), HSO(-), H2NO(-)) in the S(N)2 reactions toward NR2Cl (R = H, Me) and RCl (R = Me, i-Pr) using the G2(+)M theory. An enhanced reactivity induced by the α-atom is found in all examined systems. The magnitude of the α-effect in the reactions of NR2Cl (R = H, Me) is generally smaller than that in the corresponding S(N)2 reaction, but their variation trend with the identity of α-atom is very similar. The origin of the α-effect of the S(N)2@N reactions is discussed in terms of activation strain analysis and thermodynamic analysis, indicating that the α-effect in the S(N)2@N reactions largely arises from transition state stabilization, and the "hyper-reactivity" of these α-Nus is also accompanied by an enhanced thermodynamic stability of products from the n(N) → σ*(O-Y) negative hyperconjugation. Meanwhile, it is found that the reactivity of oxy-Nus in the S(N)2 reactions toward NMe2Cl is lower than toward i-PrCl, which is different from previous experiments, that is, the S(N)2 reactions of NH2Cl is more facile than MeCl.