Nab-paclitaxel plus platinum versus paclitaxel plus platinum as first-line therapy in patients with metastatic or recurrent cervical cancer.

PURPOSE: This study aimed to assess the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus platinum versus paclitaxel plus platinum as first-line therapy in patients with metastatic or recurrent cervical cancer. METHODS: Between October 2020 and March 2022, consecutive patients with diagnosed with metastatic or recurrent cervical cancer were retrospectively recruited in our hospital. Fifty-four patients were treated with nab-paclitaxel plus cisplatin or carboplatin. Twenty-four patients were treated with paclitaxel plus cisplatin or carboplatin. A propensity score matching (PSM) analysis was done using a multivariable logistic regression model. The two groups were compared for objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in the raw and matched dataset. RESULTS: The nab-paclitaxel group showed a higher ORR than the paclitaxel group both in the raw dataset (72.2% vs. 45.8%; P = 0.025) and matched dataset (81.1% vs. 47.6%; P = 0.008). The median PFS was significantly longer in the nab-paclitaxel group than in the paclitaxel group both in the raw and matched dataset (12 vs. 7 months; P < 0.05). The median OS was not reached in the nab-paclitaxel group compared with 15 months in the paclitaxel group, with a trend toward prolongation. The most common toxicity was hematological adverse events, including grade 3-4 neutropenia, grade 3 anemia and thrombocytopenia in both groups and no statistical differences were observed between the groups (all P > 0.05). CONCLUSION: Compared with paclitaxel plus platinum, nab-paclitaxel plus platinum may be an effective and tolerable option as first-line therapy for patients with metastatic or recurrent cervical cancer.

Development and validation of a cost-effective virtual reality educational tool to reduce anxiety and improve set-up accuracy in radiotherapy patients.

PURPOSE: This study proposes a cost-effective method for educating radiotherapy patients through an immersive virtual reality (VR) system. METHODS: The VR educational tool comprises VR glasses, a handheld controller, the scientific knowledge of radiotherapy, radiotherapy demonstration, and an audio introduction. To verify its efficacy, 120 radiotherapy patients with tumors were prospectively enrolled and divided into the control group or VR intervention group. After the first treatment, set-up errors, including three translation errors and three rotation errors, were recorded in six directions. In addition, participants were required to complete a questionnaire before radiotherapy to assess anxiety and understanding degrees. The questionnaire was scored using a five-point Likert Scale. Finally, Spearman's rank correlation test was used to evaluate set-up errors and questionnaire scores. RESULTS: The set-up errors are significantly reduced in AP, SI, total translation, Roll and total rotation in the intervention group compared with the control group (p < 0.05). The scores are higher in the intervention group than in the control group in question 1 (2.1 ± 0.58 vs. 3.3 ± 0.55), question 2 (1.3 ± 0.44 vs. 2.5 ± 0.65), question 4 (2.2 ± 0.65 vs. 3.2 ± 0.82), question 5 (1.8 ± 0.59 vs. 3.1 ± 0.79), and all subscales (5.5 ± 1.2 vs. 8.9 ± 1.3 and 6.4 ± 1.3 vs. 9.2 ± 1.5). The scores of high, moderate, and low correlation are 47 (74%), 15 (23%), and 2 (3%) for the control group and 44 (69%), 17 (26%), and 3 (5%) for the intervention group, respectively. CONCLUSION: The VR educational tool can significantly improve comprehension and reduce anxiety. There is a strong correlation between set-up errors and questionnaire scores. The VR educational tool may help reduce set-up errors for radiotherapy patients.

LncRNA GAS5 enhances radiosensitivity of hepatocellular carcinoma and restricts tumor growth and metastasis by miR-144-5p/ATF2.

BACKGROUND: This study aimed to evaluate the biologic role of growth arrest-specific 5 (GAS5) in radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The levels of GAS5, miR-144-5p, and activating transcription factor 2 (ATF2) were quantified in HCC tissues and cell lines. RNA immunoprecipitation (RIP) and RNA pull-down assays were used to test the interaction between GAS5 and miR-144-5p. The regulatory relationship between miR-144-5p and ATF2 was identified by the dual-luciferase reporter (DLR) assay. A nude mouse model of HCC was induced to verify the effect of GAS5 on radiosensitivity of HCC in vivo. RESULTS: Lower levels of GAS5 and ATF2, and higher levels of miR-144-5p, were found in radiation-resistant human HCC tissues and cell lines. Overexpression of ATF2 or GAS5 enhanced the radiosensitivity of HCC cell lines, while knockdown of ATF2 or GAS5 decreased the radiosensitivity. In addition, GAS5 acted as a miR-144-5p sponge, and miR-144-5p inversely regulated ATF2. Also, GAS5 mediated ATF2 levels through miR-144-5p, and increased the radiosensitivity of HCC by suppressing miR-144-5p both in vivo and in vitro. CONCLUSION: Overexpression of GAS5 upregulates ATF2 through miR-144-5p and is able to enhance the radiosensitivity of HCC.

Long noncoding RNA HOXC-AS3 enhances the progression of cervical cancer via activating ErbB signaling pathway.

Emerging evidence reveals that long noncoding RNAs (lncRNAs) contribute to human tumorigenesis. Nevertheless, the function of HOXC cluster antisense RNA 3 (HOXC-AS3) in human cervical cancer (CC) remains largely unknown. The levels of HOXC-AS3, miR-105-5p and SOS1 in CC tissues and cells were monitored by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Gain- and loss-of-function experiments were conducted to verify the function of HOXC-AS3 and miR-105-5p in CC cells. Meanwhile, cell proliferation, apoptosis, migration and invasion were examined by the cell counting kit-8 (CCK8) experiment, colony formation assay, flow cytometry and Transwell assay. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to test the regulatory interaction of HOXC-AS3, miR-105-5p and SOS1. In addition, in vivo experiment was performed to certain the role of HOXC-AS3 in tumorigenesis of CC. HOXC-AS3 was overexpressed in CC tissues (vs. adjacent normal tissues) and CC cells. Besides, the higher HOXC-AS3 profile was associated with the poorer clinical prognosis of CC patients. Overexpression of HOXC-AS3 promoted cell growth, migration and invasion, hampered apoptosis, whereas knocking down HOXC-AS3 exhibited the reverse effects. MiR-105-5p was a downstream target of HOXC-AS3, and it mediated the HOXC-AS3-induced oncogenic effects. Mechanistically, the bioinformatic analysis illustrated that SOS1 was targeted by miR-105-5p. Up-regulating SOS1 heightened the growth, migration and invasion of CC cells by enhancing the ErbB signaling pathway, which was reversed by miR-105-5p. Up-regulated HOXC-AS3 aggravates CC by promoting SOS1 expression via targeting miR-105-5p.

Abemaciclib sensitizes HPV-negative cervical cancer to chemotherapy via specifically suppressing CDK4/6-Rb-E2F and mTOR pathways.

Cervical cancer is the second most common malignancy in women, and the novel therapeutic treatment is needed. Abemaciclib is a FDA-approved drug for breast cancer treatment. In this work, we identified that abemaciclib has potent anti-cervical cancer activity. We demonstrate that abemaciclib is the most effective drug against human papillomavirus (HPV)-negative cervical cancer cells compared to ribociclib and palbociclib, with its IC50 at nanomolar concentration range. This is achieved by the inhibition of proliferation and induction of apoptosis, through specifically suppressing CDK4/6-Rb-E2F and mTOR pathways by abemaciclib in HPV-negative cervical cancer cells. Of note, the combination of abemaciclib with paclitaxel and cisplatin at sublethal concentration results in much greater efficacy than chemotherapy alone. In addition, we confirm the efficacy of abemaciclib and its combination with paclitaxel or cisplatin at the doses that are not toxic to mice in HPV-negative cervical cancer xenograft mouse model. Interestingly, we show that abemaciclib and other CDK4/6 inhibitors are not effective in targeting HPV-positive cervical cancer cells, and this is likely to be associated with the high p16 and low Rb expression in HPV-positive cervical cancer cells. Our work is the first to provide the preclinical evidence to demonstrate the potential of abemaciclib for the treatment of HPV-negative cervical cancer. The mechanism analysis highlights the therapeutic value of inhibiting CDK4/6 in HPV-negative but not HPV-positive cervical cancer.

Cardamonin Promotes the Apoptosis and Chemotherapy Sensitivity to Gemcitabine of Pancreatic Cancer Through Modulating the FOXO3a-FOXM1 Axis.

Cardamonin (CAR), a flavone existing in the Alpinia plant, has been found to modulate multiple biological activities, including antioxidant, anti-inflammatory, and anti-tumor effects. Nevertheless, the influence of CAR on pancreatic cancer (PC) is less understood. Here, we conducted in vitro and in vivo experiments to explore the functions of CAR on PC cells' proliferation, apoptosis and chemosensitivity to gemcitabine (GEM). The growth of PC cells (including PANC-1 and SW1990) was evaluated by the cell counting kit-8 assay, colony formation assay and xenograft tumor experiment. Besides, the apoptosis was determined by flow cytometry and western blot (WB). Moreover, the FOXO3a-FOXM1 pathway expression was tested by reverse transcription-polymerase chain reaction and WB. Our data suggested that CAR restrained cell proliferation, growth and expedited apoptosis both in vitro and in vivo. Moreover, CAR sensitized PC cells to GEM. Mechanistically, CAR heightened FOXO3a while repressed FOXM1. Further loss-of-function assays revealed that down-regulating FOXO3a markedly dampened the anti-tumor effect induced by CAR and accelerated the FOXM1 expression. Our data confirmed that CAR exerted an anti-tumor function in PC dependently by modulating the FOXO3a-FOXM1 axis.

Gold nanorod delivery of LSD1 siRNA induces human mesenchymal stem cell differentiation.

Over the past decade, theranostic nanoparticles with microsize and multifunctional ability have emerged as a new platform in biomedical field, such as cancer therapy, optical imaging and gene therapy. Gene therapy has been recently shown as a promising tool for tissue engineering as safe and effective nanotechnology-based delivery methods are developed. Controlling adhesion and differentiation of stem cells is critical for tissue regeneration. In this study, we have developed poly-sodium 4-styrenesulfonate (PSS) and poly-allylamine hydrochloride (PAH) coated AuNR-based nanocarriers, which are capable of delivering small interfering RNA (siRNA) against LSD1 to induce the differentiation of human mesenchymal stem cells. To further study the mechanism, we tested the stemness and differentiation genes and found that they have been changed with LSD1 down-regulation. In addition, with the hepatocyte growth factor (HGF), LSD1 siRNA delivery by AuNRs could promote the differentiation of the human mesenchymal stem cells (human MSCs) into a hepatocyte lineage in vitro. Our results suggest for the first time use of AuNRs as nanocarriers of delivery LSD1 siRNA to induce the differentiation of human MSCs into a hepatocyte lineage, and envision the potential application of nanotechnology in tissue remodeling (such as liver and bone) in vivo, eventually translating to clinical applications.

Two distinct modes of hypoosmotic medium-induced release of excitatory amino acids and taurine in the rat brain in vivo.

A variety of physiological and pathological factors induce cellular swelling in the brain. Changes in cell volume activate several types of ion channels, which mediate the release of inorganic and organic osmolytes and allow for compensatory cell volume decrease. Volume-regulated anion channels (VRAC) are thought to be responsible for the release of some of organic osmolytes, including the excitatory neurotransmitters glutamate and aspartate. In the present study, we compared the in vivo properties of the swelling-activated release of glutamate, aspartate, and another major brain osmolyte taurine. Cell swelling was induced by perfusion of hypoosmotic (low [NaCl]) medium via a microdialysis probe placed in the rat cortex. The hypoosmotic medium produced several-fold increases in the extracellular levels of glutamate, aspartate and taurine. However, the release of the excitatory amino acids differed from the release of taurine in several respects including: (i) kinetic properties, (ii) sensitivity to isoosmotic changes in [NaCl], and (iii) sensitivity to hydrogen peroxide, which is known to modulate VRAC. Consistent with the involvement of VRAC, hypoosmotic medium-induced release of the excitatory amino acids was inhibited by the anion channel blocker DNDS, but not by the glutamate transporter inhibitor TBOA or Cd2+, which inhibits exocytosis. In order to elucidate the mechanisms contributing to taurine release, we studied its release properties in cultured astrocytes and cortical synaptosomes. Similarities between the results obtained in vivo and in synaptosomes suggest that the swelling-activated release of taurine in vivo may be of neuronal origin. Taken together, our findings indicate that different transport mechanisms and/or distinct cellular sources mediate hypoosmotic medium-induced release of the excitatory amino acids and taurine in vivo.

[Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin in the treatment of stage III non-small cell lung cancer.].

BACKGROUND: Concurrent chemoradiotherapy is regarded as the standard care for locally advanced non-small cell lung cancer at present. This paper is designed to evaluate the efficacy and toxicity of low-dose weekly docetaxel (DTX) with concurrent chemoradiotherapy followed by consolidation chemotherapy with DTX and cisplatin for unresectable stage III non-small cell lung cancer(NSCLC). METHODS: 44 previously untreated patients with stage III NSCLC were randomized into low-dose weekly DTX group and control group concomitant with radiotherapy. Both groups were treated by the standard fractionation schedule with three-dimensional conformal radiotherapy. An involved-field irradiation technique was performed. Gross tumor and metastatic lymph nodes were irradiated to a total dose of 66 Gy-70 Gy. Patients in the former group received chemotherapy with DTX 20 mg.m(-2).w(-1), and the other group patients received DTX 60 mg/m(2) on day 1 and DDP 30 mg/m(2) on day 1-3 every 21 days. All patients received consolidation chemotherapy with DP regime after chemoradiotherapy for no more than 4 cycles. RESULTS: The overall response rates of patients in the low-dose weekly DTX group and control group were 81.8% with 27.3% CR(complete response) and 86.4% with 27.3% CR respectively (Chi-Square=0.120, P=0.942). After a median follow-up of 20 months, the median survival time was 20 months and 17 months respectively. The 1-, 2- year survival rates of patients in low-dose weekly DTX group and control group were 69.8%, 48.1% versus 66.5%, 40.2% respectively;there was no difference between two groups. Grade 3 or 4 neutropenia and esophagitis occurred in 26.3%, 14.3% and 15.8%, 28.6% respectively (Chi-Square=0.765, P=0.382;Chi-Square=1.108, P=0.292).Grade 3 and 4 pulmonary toxicity was unusual. CONCLUSIONS: Concurrent chemoradiotherapy with low-dose weekly docetaxel followed by consolidation chemotherapy with docetaxel and cisplatin is highly active with manageable toxicity in patients with stage III NSCLC.

Effect of qi-tonifying and stasis-eliminating therapy on expression of vascular endothelial growth factor and its receptors Flt-1, Flk-1 in the brain of intracerebral hemorrhagic rats.

OBJECTIVE: To investigate the effects and mechanism of qi-tonifying and stasis-eliminating (QTSE) therapy on the expression of vascular endothelial growth factor (VEGF) and its receptors Flt-1 and Flk-1 in the brains of intracerebral hemorrhagic (model) rats. METHODS: One hundred and eighty Sprague-Dawley rats were randomly divided into six groups: the normal group (n=5), the sham-operative (SO) group (n=35), the model group (n=35), the QTSE group (n=35), the QT group (n=35) and the SE group (n=35). All the rats except those in the normal group and SO group were established into an intracerebral hemorrhage(ICH) model by intracerebral injection of collagenase type VII and the latter three were orally administered with Buyang Huanwu Decoction (a classical recipe for QTSE) or with some of its components for qi-tonification and for stasis-elimination, respectively. To the other three groups, normal saline solutions were given instead. Behavioral tests were carried out in the animals randomly chosen from each group on days 1, 2, 4, 7, 14, 21 and 28 after modeling. The expressions of VEGF, Flk-1 and Flt-1 were determined by immunohistochemistry and the number of vascular segments with positive expression in the injured brain area of the rats was calculated. RESULTS: From day 7 onwards, the asymmetric forelimb use rate in the QTSE group recovered more significantly than that in the other model groups. In the model group, the expressions of VEGF, Flk-1 and Flt-1 appeared on day 1 and reached a peak on day 21, then weakened gradually. In the QTSE group, as compared with the other model groups, a higher level of VEGF expression was shown from day 7 (P<0.01) and a higher level of Flt-1 expression was shown from the 7th day to the 21st day (P<0.01). CONCLUSION: QTSE therapy can up-regulate the expressions of VEGF and its receptors (Flk-1 and Flt-1) and improve the recovery of kinetic function in the ICH rats, which may be correlated with its action in modulating vascular regeneration to promote the reconstruction of microvascular networks in the damaged areas.

Behavioral and histological neuroprotection by tamoxifen after reversible focal cerebral ischemia.

We have previously shown that tamoxifen can reduce infarct sizes measured by 2,3,5,-triphenyltetrazolium chloride (TTC) staining at 72 h after 2 h of reversible middle cerebral artery occlusion (rMCAo) in rats. In this study, we tested whether improvement is found in both behavioral measures of protection and by histological measures of infarcted tissue at 7 and 14 days after 2 h rMCAo. Tamoxifen (10 mg/kg) was given once by intravenous injection 1 h after reperfusion, i.e. 3 h after initiation of rMCAo. Neurobehavioral deficits were evaluated daily for 1 week or 2 weeks followed by infarct volumes measurements by hematoxylin-eosin (HE) staining. Tamoxifen-treated rats had significantly improved neurobehavioral deficit scores when evaluated daily throughout the 1 week or 2 week periods and showed significantly reduced median infarct volumes measured after 1 week and 2 weeks. Median infarct values were 149 mm3 (interquartile range, IQR: 92 to 258) and 124 mm3 (IQR: 69 to 174) for the 1 and 2 week vehicle groups, respectively, compared with 5 mm3 (IQR: 3 to 16) and 4 mm3 (IQR: 0 to 48) for the comparable treated groups (both P < 0.05, Mann-Whitney test), giving a reduction of more than 90% in both cases. Thus, a single administration of tamoxifen given 3 h after initiation of rMCAo is extremely effective in producing long-term neuroprotection as assessed by neurobehavioral measures and histopathology in experimental stroke in rats. If these results are extrapolatable to human stroke, these data indicate that tamoxifen may be a useful neuroprotectant.

[Thinking on the assessment of clinical therapeutic effectiveness of TCM].

How to assess the therapeutic effectiveness of TCM is the focus of this paper, the trend of study on standard for therapeutic effectiveness assessment and application of standard for disease combined with symptom diagnosis and treatment were described. Taking the study on standard for TCM syndrome of Gan as an example, the basic principle and existing problem in standard formulation were pointed out. The possibility in establishing the therapeutic effectiveness assessment system of TCM by using the quantified scale for therapeutic effectiveness assessment as a tool, i.e., the theoretical design of the scale formation should be in accord with the theories of TCM, and followed with scientific measuring principle, based on the sample investigation to establish the database of quantified scale, to make sure the scale that having corresponding checking process and scoring criteria so as to make the scale meeting the need of reliability and validity. It was also pointed owt that the scale should be used in combination with the standard for syndrome differentiation, thus, the scientific, practical therapeutic effectiveness assessment system of TCM could be built up.

Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra.

BACKGROUND AND PURPOSE: Release of excitatory amino acids (EAA) is considered a cause of neuronal damage in ischemia. We investigated the sources and mechanisms of EAA release using microdialysis in regions of incomplete ischemia where perfusion was reduced by 50% to 80%, by applying inhibitors of volume-regulated anion channels (VRACs) and the GLT-1 glutamate transporter. METHODS: Reversible middle cerebral artery occlusion (rMCAo) was induced in anesthetized rats using the intraluminal suture technique. Microdialysate concentrations of glutamate, aspartate, and taurine were measured before, during 2 hours of rMCAo, and for 2 hours after rMCAo. Vehicle, dihydrokainate (DHK, 1 mmol/L), a GLT-1 inhibitor, or tamoxifen (50 micromol/L), a VRAC inhibitor, were administered continuously via the dialysis probes starting one hour prior to ischemia. RESULTS: During incomplete ischemia, dialysate glutamate levels averaged 1.74+/-0.31 micromol/L (SEM) in the control group (n=8), 2.08+/-0.33 micromol/L in the DHK group (n=7), and were significantly lower at 0.88+/-0.30 micromol/L in the tamoxifen group (n=9; P<0.05). As perfusion returned toward baseline levels, EAA levels declined in the vehicle and tamoxifen-treated animals but they remained elevated in the DHK-treated animals. CONCLUSIONS: In contrast to previous results in severely ischemic regions, DHK did not reduce EAA release in less severely ischemic brain, suggesting a diminished role for transporter reversal in these areas. These findings also support the hypothesis that in regions of incomplete ischemia, release of EAAs via VRACs may play a larger role than reversal of the GLT-1 transporter.

Neuroprotective activity of tamoxifen in permanent focal ischemia.

OBJECT: The authors have previously shown that tamoxifen is effective in protecting brain tissue from ischemic injury in a rat model of reversible focal ischemia. In this study the authors tested whether similar protective effects are found in a rat model of permanent focal ischemia (permanent middle cerebral artery [MCA] occlusion). METHODS: Tamoxifen (20 mg/kg) was given either before or at 1, 3, or 6 hours after permanent MCA occlusion in rats, with sustaining doses given every 12 hours thereafter. The median infarct volume measured after 72 hours was 113 mm3 for the vehicle (dimethyl sulfoxide) groups, compared with 31 mm3 for pretreatment, and 14, 27, and 98 mm3 for treatment beginning at 1, 3, and 6 hours, respectively, after permanent MCA occlusion. The infarct reductions in the pretreated and 1- and 3-hour post-MCA occlusion treatment groups were statistically significant (p < 0.05). At 3 hours after permanent MCA occlusion, tamoxifen also significantly reduced the infarct size at a lower dose of 5 mg/kg but not at 1 mg/kg; the same sustaining doses of 5 and 1 mg/kg were given every 12 hours. CONCLUSIONS: Tamoxifen is as effective in a permanent model of focal ischemia as it is in the reversible model, and the therapeutic window of 3 hours after initiation of ischemia is identical. This effectiveness is likely due to several properties of the drug, including its known ability to cross the blood-brain barrier. Because tamoxifen has been administered safely in humans for treatment of gliomas at similarly high doses to those used in this study, it may be clinically useful as a treatment for ischemic stroke.

Multiple organ dysfunction syndrome due to ingestion of fish gall bladder.

OBJECTIVE: To investigate changes in renal function, urine N-acetyl-beta-D-glucosaminidase enzyme (N-AG),liver function, myocardial enzymes, the pathology of renal damage and the mechanism of acute renal failure (ARF) associated with fish gall bladder poisoning. METHODS: Eleven patients with acute fish gall bladder poisoning were consecutively admitted to our hospital from September 1997 to October 1999. Renal function, urine N-AG enzyme, liver function, and myocardial enzymes were assayed before and after treatment. One patient consented to a kidney biopsy and the pathology of renal damage was observed under light and electron microscopes. RESULTS: All patients had multiple organ dysfunction syndrome (MODS) and 11 patients suffered from ARF. Ten patients had liver dysfunction, ten patients had poisonous myocarditis, and 8 patients had gastrointestinal dysfunction. Renal function, urine N-AG enzyme, liver function, and myocardial enzymes were significantly improved after treatment compared with those of before treatment (P < 0.05). Kidney biopsy showed that the main damage site was the proximal renal tubule. All eleven patients recovered and were discharged from the hospital. CONCLUSIONS: Ingestion of fish gall bladder leads to kidney damage, as well as liver, heart and gastrointestinal tract injury. The mechanism of acute renal function failure is the serious tubular damage, confirming the location of kidney damage. Necrosis of the proximal tubules plays an important role in the development of ARF. Immediate hemodialysis is the most effective treatment.