Combined Treatment Research Articles

Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIV-positive individuals.

Sustained viral suppression in patients with multidrug-resistant (MDR) human immunodeficiency virus (HIV) infection remains difficult; accordingly, agents targeting different steps in the HIV life cycle are needed. Ibalizumab, a humanized immunoglobulin G4 monoclonal antibody, is a cluster of differentiation (CD4)-directed post-attachment inhibitor. In this Phase IIb study, 113 individuals with MDR HIV-1 and limited treatment options were assigned an optimized background regimen (OBR) and randomized to either 800 mg ibalizumab every two weeks (q2wk; n=59) or 2,000 mg ibalizumab every four weeks (q4wk; n=54) up to Week 24. Viral loads (VL) below the detection limit were achieved in 44% and 28% of patients in the 800 mg q2wk and 2,000 mg q4wk groups, respectively, at Week 24. Mean (standard deviation) VL (log10 copies/mL) decreased from Baseline (4.6(0.8), 800 mg q2wk; 4.7(0.7), 2,000 mg q4wk) to Week 2, with the reduction maintained through Week 24 (2.9(1.5), 800 mg q2wk; 3.2(1.4), 2,000 mg q4wk). Baseline CD4+ counts were 80.5 and 54.0 cells/μL in the 800 mg q2wk and 2,000 mg q4wk groups, respectively. Mean CD4+ T-cell count was increased at Week 24 in both groups. No serious adverse events were related to ibalizumab. In heavily treatment-experienced patients with HIV (PWH) at a more advanced baseline disease severity, clinically significant response rates at Week 24 were achieved with ibalizumab plus OBR. Ibalizumab's unique mechanism of action and lack of cross-resistance to other antiretroviral agents make it an important component of combination treatment regimens for PWH with limited treatment options.

Lynch Syndrome-associated Genomic Variants.

Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome. We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer. Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression. This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndrome-associated cancers.

FACT inhibitor CBL0137, administered in an optimized schedule, potentiates radiation therapy for glioblastoma by suppressing DNA damage repair.

Standard-of-care for glioblastoma remains surgical debulking followed by temozolomide and radiation. However, many tumors become radio-resistant while radiation damages surrounding brain tissue. Novel therapies are needed to increase the effectiveness of radiation and reduce the required radiation dose. Drug candidate CBL0137 is efficacious against glioblastoma by inhibiting histone chaperone FACT, known to be involved in DNA damage repair. We investigated the combination of CBL0137 and radiation on glioblastoma. In vitro, we combined CBL0137 with radiation on U87MG and A1207 glioblastoma cells using the clonogenic assay to evaluate the response to several treatment regimens, and the Fast Halo Assay to examine DNA repair. In vivo, we used the optimum combination treatment regimen to evaluate the response of orthotopic tumors in nude mice. In vitro, the combination of CBL0137 and radiation is superior to either alone and administering CBL0137 two hours prior to radiation, having the drug present during and for a prolonged period post-radiation, is an optimal schedule. CBL0137 inhibits DNA damage repair following radiation and affects the subcellular distribution of histone chaperone ATRX, a molecule involved in DNA repair. In vivo, one dose of CBL0137 is efficacious and the combination of CBL0137 with radiation increases median survival over either monotherapy. CBL0137 is most effective with radiation for glioblastoma when present at the time of radiation, immediately after and for a prolonged period post-radiation, by inhibiting DNA repair caused by radiation. The combination leads to increased survival making it attractive as a dual therapy.

A Photoactivatable Self-Assembled Nanoagonist for Synergistic Therapy against Pancreatic Ductal Adenocarcinoma.

Immunotherapy has revolutionized the cancer treatment paradigm, yet efficient immunotherapeutic responses against immune-cold/desert cancers remain challenging. Herein, we report that photoactivatable nanoagonists yield a potent antitumor synergy of photoimmunotherapy against pancreatic ductal adenocarcinoma (PDAC). The nanoagonist was fabricated by assembling an amphiphilic boron dipyrromethene-derived polymer conjugated with a Toll-like receptor agonist via a photocleavable linker and stimulator of interferon genes agonist. The nanoagonist enables light-induced generation of reactive oxygen species and on-demand release of the agonists to yield synergistic photoimmunotherapy. The produced tumor antigens promote dendritic cell maturation, which is further amplified by these agonists for eliciting adaptive immunity, accompanied by apparently abscopal and long-term memory effects. The nanoagonist further alleviates the fibrosis of tumor stroma and the immunosuppressive microenvironment, leading to the deep infiltrations of clinically used therapeutics and immune cells to yield preferable combinational treatments against PDAC models. These results provide valuable insights into activatable nanoparticles for cancer therapy against immune-desert cancers.

Evaluation of Five Sesame (Sesamum Indicum L.) Varieties Under Varying Fertilizer Rates and Establishment Methods for Growth and Yield in Anyigba, Kogi State, Nigeria

Global sesame seed market is projected to have USD 7.24 billion in consumption value by 2024. However, its supply has not been able to match the demand due to several constraints to its production. This study was conducted at the Prince Abubakar Audu University Research and Demonstration Farm, during the 2023 cropping season to evaluate five sesame varieties for growth and yield under varying fertilizer rates and establishment methods. Treatment consisted of five sesame varieties, two establishment methods, and three fertilizer levels respectively combined factorially to obtain a total of thirty factorial treatment combinations and laid out in a Randomized Complete Block Design (RCBD) with three replicates. Results showed that varieties differed significantly (P < 0.05) in growth, yield and yield characters. YANDEV55 produced the widest leaf area at 9WAS, NCRIBEN-02M produced the highest number of leaves per plant (36) at 12WAS. The same variety (NCRIBEN-02M) consistently produced the tallest stems (42.48, 56.10, 80.48 & 93.46 cm) at 3, 6, 9 & 12WAS. YANDEV55 produced 73.6 % germination which was highest amongst others. E8 produced the highest number of capsule/plant (23.3) and number of seeds/plant (1428.94). NCRIBEN-05E performed optimally in yield characters such as total plant biomass yield (2908.0g/plot) and final seed yield (887.9kgha-1). NCRIBEN-02M had the highest haulm yield (33.0g/plot) while NCRIBEN-01M had the longest days (54.16) to 50% anthesis. Seed/capsule and Harvest index were not significantly affected by varieties. Broadcast method produced significantly widest leaf areas of 53.9 and 40.5 cm2 at 6 and 12 WAS respectively, higher number of leaves (18.0) at 3WAS. Drilling method of crop establishment produced the highest biomass yield (2894.6g/plot) and final seed yield (879.2 kgha-1). Similarly, fertilizer rates affect growth and yield characters; 100 kg NPKha-1 produced the widest leaf area, tallest plants and highest number of leaves/plant at all stages of sampling. These were at par with values obtained when plots were treated with 150kg NPKha-1. Alternatively, highest number of capsules/plant (22.4), seeds/capsule (62.46), seeds/plant (1502.73), total plant biomass yield (2879.7g/plot), haulm yield (33.0g/plot), final seed yield (870.7kgha-1) and longest number of days to 50% anthesis (53.6) were all obtained when plots were treated with 150 kgha-1 but was at par with 100kg NPKha-1. Fertilizer rates did not affect the establishment count and harvest index. The best variety with respect to yield/ha is NCRIBEN-02M, Application of 100 kg NPK/ha appears maximum for optimum yield of the crop, drilling appears to produce higher yield than broadcast for some varieties with an overall marginal increase of 8.4 % over broadcast and thus recommended for Anyigba environment. An economic study of the cost implication for both operations (drilling and broadcast) could be embarked upon to ascertain the veracity of this assertion, more so that broadcast requires higher seed rate than drilling. Significant interaction of varieties x establishment method was also an indication that very high yielding varieties (NCRIBEN-02M and NCRIBEN-01M) do better when drilled compared to broadcast. Significant positive relationship between some growth, yield and yield characters is an indication that effective crop improvement through selection can be carried out by selecting for those characters that correlated positively with yield.

Geotechnical Forensic Investigations of a Gravity Dam: Addressing Seepage and Sliding Problems in the Basalt Foundations of Karjan Dam, Gujarat, India

Geotechnical forensic engineering plays a crucial role in identifying and mitigating potential issues in large gravity dams. The Karjan Dam in Gujarat, India, a 100-meter-high gravity dam built 38 years ago on Deccan basalt, encountered significant geotechnical challenges during construction due to early investigation oversights. These oversights failed to detect sub-horizontal weathered rock seams within the basalt during the pre-construction investigations, which could have posed significant seepage and sliding risks during the dam's operation. Subsequent detailed investigations during the construction phase revealed that these seams extended throughout the foundations of the dam blocks. In-situ shear tests were conducted to determine the shear parameters, namely cohesion (C) and the angle of internal friction (ϕ) of the seams. The test results indicated low shear strength parameters, necessitating a re-evaluation of the dam's safety. Stability analysis revealed that the spillway and certain non-overflow blocks were at risk of sliding and seepage after reservoir filling. To address these geotechnical challenges, a combination of treatments—including concrete shear keys, grouting, and design enhancements—was implemented to prevent sliding and control seepage. The timely forensic investigation and treatment during the construction stage ensured the dam's safety, which has operated without issues since 1986. This study underscores the critical importance of integrating engineering and geological assessments at various stages of dam construction. Re-evaluating and addressing evolving foundation conditions, particularly during construction, is essential for applying effective treatments to prevent dam failure during operation. The findings from this case study provide valuable geotechnical insights required for enhancing the safety and resilience of dam infrastructure globally.

Patient-derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways.

Malignant ascites is commonly produced in advanced epithelial ovarian cancer (EOC) and serves as unique microenvironment for tumour cells. Acellular ascites fluid (AAF) is rich in signalling molecules and has been proposed to play a role in the induction of chemoresistance. Through in vitro testing of drug sensitivity and by assessing intracellular phosphorylation status in response to mono- and combination treatment of five EOC cell lines after incubation with AAFs derived from 20 different patients, we investigated the chemoresistance-inducing potential of ascites. We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFκB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1. Treatments with SCDs were effective in reducing cell viability in only a third of 30 clinically relevant conditions examined, defined as combinations of drugs, different cell lines and AAFs. Combinations of SCDs and novel therapeutics such as trametinib, fludarabine or rapamycin were superior in another third. Notably, we could nominate effective treatment combinations in almost all conditions except in 4 out of 30 conditions, in which trametinib or fludarabine showed higher efficacy alone. Taken together, our study underscores the importance of the molecular characterisation of individual patients' AAFs and the impact on treatment resistance as providing clinically meaningful information for future precision treatment approaches in EOC.

Combined treatment of wounded with traumatic aneurysm of posterior communicating artery complicated by intraventricular hemorrhage

Cerebral blood vessel trauma (CBVT) is a serious condition of craniocerebral injury. According to literature data, different varieties of CBVT in penetrating gunshot craniocerebral injuries are found in 30–45 % of cases. Traumatic pseudoaneurysms are the most common finding in late evaluation and can lead to life-threatening episodes of intracranial hemorrhage.In addition, CBVT includestraumatic occlusion, dissection of vessels, rupture of cerebral arteries, formation of arteriovenous fistulas (carotid-cavernous anastomoses), venous stasis, etc. Injured persons with traumatic dissection and injury of vertebrobasilar pool have the highest risks of lethal outcome. There are no largerandomised trials and national recommendations for the treatment of CBVT, individual observations and small series of clinical cases have been published. In this connection, there is a need for a detailed analysis of all clinical cases, the development of tactics for early diagnosis and an algorithm for the treatment of wounded with CBVT.The article presents a review of the literature data that characterizes the current understanding of CBVT, and a clinical case of traumatic occlusion of the middle cerebral artery and pseudoaneurysm of the posterior communicating artery in a wounded man with a gunshot penetrating cranioorbital wound, who was treated at the neurosurgical center of the N.N. Burdenko Main Military Clinical Hospital.In the early period after the injury, the patient underwent endovasal occlusion of a traumatic aneurysm of the posterior connective artery by microspirals followed by local thrombolysis of intraventricular hematomas through a ventricular catheter. The catamnesis was 150 days, the score on the modified Rankin scale was 3, the Glasgow outcome scale extended was 5.

Evaluation of Tractor Mounted Axial Flow Combine Harvester for Mung Bean (Vigna radiata L.)

A cost-effective, tractor mounted axial flow combine harvester designed to minimize harvesting losses was evaluated. Performance evaluation of the machine was done on summer mung bean (Vigna radiata L. Wilczek) under various operational conditions: three forward speeds (FS): 2.1, 3.0, and 4.8 km h-1, three-cylinder peripheral speeds (PS): 11.08, 13.16, and 14.79 m s-1, and days after irrigation (DAI): 2, 4, and 6 days after last irrigation. Threshing efficiency, cleaning efficiency, broken percentage, shattering losses, and non-collectable losses were estimated. Cost of operation of the combine harvester was compared with manual harvesting and subsequent threshing using a spike tooth type thresher. The results show that the threshing efficiency and grain breakage increased by 1.1% and 1.01%, respectively, with an increase in DAI and PS, however, both these parameters decreased with an increase in FS. The non-collectable loss increased by 0.9% with an increase in FS and DAI; however, PS did not affect the non-collectable losses. The cleaning efficiency increased with an increase in FS, but it decreased with an increase in PS and DAI. The shattering loss increased with an increase in FS and DAI, although PS had no impact. The best combination of operational variables for threshing operation was found for treatment combination of 6 days after last irrigation, with a cylinder peripheral speed of 14.79 m s-1 and a forward speed of 3.0 km h-1. At this combination, threshing efficiency, non-collectable losses, grain breakage, and cleaning efficiency were 99.28%, 4.53%, 2.96%, and 95.89%, respectively. This combine-harvester saved 91.75% in labor costs and 53.71% in harvesting costs compared to the combination of manual harvesting and subsequent threshing using a spike tooth type thresher.

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

BackgroundThe plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or ‘endozepine’) increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.MethodsWe measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.ResultsCirculating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.ConclusionThese findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-Carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia

Synergetic inhibition of FMS-like tyrosine kinase 3 (FLT3) and histone deacetylase (HDAC) by small molecule chimera presents a promising therapeutic approach for acute myeloid leukemia (AML) with FLT3 mutations. In this study, we first observed that the combined use of FLT3 inhibitor gilteritinib and HDAC inhibitor vorinostat increased the survival rate of leukemia xenograft mouse model. Then, we employed a pharmacophore fusion strategy to develop a novel series of FLT3/HDAC dual inhibitors. Among them, compound 25h demonstrated superior inhibitory activity against both FLT3 and HDAC. In particular, compound 25h exhibited enhanced anti-proliferation activity against MOLM-13 cells in comparison to gilteritinib, vorinostat, and their combination, while maintaining reduced cytotoxicity towards normal cells. Mechanistically, the heightened anti-tumor effect of compound 25h was attributed to its more potent regulation of intracellular pathways, notably phosphorylation of ERK, compared to single drug and combination treatments. Furthermore, compound 25h demonstrated superior anti-tumor efficacy in the MOLM-13 xenograft model compared to combination therapy, along with reduced in vivo toxicity. To conclude, we have identified a novel FLT3/HDAC dual inhibitor that could serve as a potential candidate for the treatment of AML.

Improving mode I fracture response of glass fiber-epoxy composite adhesive joints using sanding treatment and MWCNTs inclusion

This study investigates the enhancement of fracture behavior in laminated composites using a combination of surface treatments and nanomaterial incorporation. The adherent material used is glass fiber-reinforced polymer (GFRP), and the surface treatment was applied to the GFRP surface. The adhesive used in the joints is an epoxy-based adhesive, which was reinforced with Multi-Walled Carbon Nanotubes (MWCNTs) to improve its mechanical properties. Initially, mechanical sanding techniques were explored, revealing significant improvements of 55% in fracture energy and 38% in load-bearing capacity with optimal 240-grit sanding. Subsequently, MWCNTs were introduced at varying weight percentages (0.1%, 0.3%, and 0.5%) into the adhesive. This combined approach aimed to synergistically examine the impact of surface pretreatments and nanoparticle integration on the fracture behavior of the GFRP joints. Results highlight the potential for fracture resistance and enhanced load-carrying capabilities in reinforced specimens, with maximum load and fracture energy improvements of up to 92% and 50%, respectively, compared to unreinforced specimens and those subjected solely to sanding treatments. Moreover, the shift in failure mode from adhesive failure to cohesive substrate failure was observed and is attributed to the enhanced bonding area created by the 240-grit sanding and the increased fracture resistance from the incorporation of 0.3 wt% MWCNTs. The inclusion of MWCNTs provides additional toughening mechanisms such as crack bridging and pull-out, which significantly increase the fracture energy. This comprehensive investigation underscores the intricate interplay between mechanical preparation and nanomaterial incorporation in significantly improving the performance of laminated composites.

Depression with comorbid juvenile-onset fibromyalgia syndrome novel treatment plan using interpersonal psychotherapy: A case report.

Fibromyalgia syndrome (FMS) affects 2% to 4% of people, with increasing prevalence in Saudi Arabia reaching 13.4%. FMS can occur in adolescents, known as juvenile-onset fibromyalgia (JFM) with comorbidities including depression, anxiety, and psychological stress. Our patient presented to the child and adolescent psychiatry clinic at King Saud University Hospital Medical City. A year before coming to our clinic, at the age of 15 she was initially diagnosed with JFM followed by a comorbid persistent depressive disorder. As a novel treatment method, a combination treatment approach was used, including a pharmacological intervention with Duloxetine, and a non-pharmacological intervention with interpersonal psychotherapy for adolescents. She completed 16 weeks of therapy while monitoring for duloxetine response and side effects. Depressive symptoms were in remission by treatment's end and continued to be in her first month posttreatment follow-up, and the FMS symptoms were also controlled. Our present case highlights a combined approach to treat depression and JFM in adolescents as a novel intervention method thus we strongly recommend utilizing it for similar cases.

Auraptene Boosts the Efficacy of the Tamoxifen Metabolites Endoxifen and 4-OH-Tamoxifen in a Chemoresistant ER+ Breast Cancer Model

Approximately 80% of breast cancer (BC) cases are estrogen receptor positive (ER+) and sensitive to hormone treatment; Tamoxifen is a prodrug, and its main plasmatic active metabolites are 4-hydroxytamoxifen (4-OH Tam) and endoxifen. Despite the effectiveness of tamoxifen therapy, resistance can be developed. An increment in eukaryotic initiation factor-4A complex (eIF4A) activity can result in tamoxifen-resistant tumor cells. For this work, we developed a cell variant resistant to 4-OH Tam and endoxifen, denominated MCF-7Var E; then, the aim of this research was to reverse the acquired resistance of this variant to tamoxifen metabolites by incorporating the natural compound auraptene. Combination treatments of tamoxifen derivatives and auraptene successfully sensitized the chemoresistant MCF-7Var E. Our data suggest a dual regulation of eIF4A and ER by auraptene. Joint treatments of 4-OH Tam and endoxifen with auraptene identified a novel focus for chemoresistance disruption. Synergy was observed using the auraptene molecule and tamoxifen-derived metabolites, which induced a sensitization in MCF-7Var E cells and ERα parental cells that was not observed in triple-negative breast cancer cells (TNBC). Our results suggest a synergistic effect between auraptene and tamoxifen metabolites in a resistant ER+ breast cancer model, which could represent the first step to achieving a pharmacologic strategy.

A novel combination therapy for ER+ breast cancer suppresses drug resistance via an evolutionary double-bind.

Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an "evolutionary double-bind", where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram.

Pharmacoeconomic evaluation of treatments for Poly Cystic Ovarian Syndrome (PCOS)

BackgroundTreatment cost and high prevalence of Poly Cystic Ovarian Syndrome (PCOS) is a very challenging issue globally. Due to this reason; current study was conducted to determine pharmaco-economy of conventional and non-conventional treatments for the management of PCOS.MethodsProspective Cross-Sectional study was conducted in the metropolitan city of Karachi from January – December 2019. Primary data of 200 PCOS patients were collected from different hospitals and clinics. An instrument was used to collect data pertaining to the direct and indirect cost associated with the disease management. Collected data was analyzed by the tools for cost analysis and software called Statistical Package of Social Sciences (SPSS) – 22.ResultsIn Cost Minimization Analysis (CMA); Allopathic treatment [Mean cost/month: PKR:4479.32 ± 350.95 (USD:27.46 ± 2.15)], Herbal treatment [Mean cost/month: PKR:1527.78 ± 78.15 (USD:9.37 ± 0.48)], Combination treatment [Mean cost/month: PKR:2803.09 ± 654.22 (USD:17.18 ± 4.01)], and Homoeopathic treatment [Mean cost/month: PKR:976.95 ± 46.19 (USD:5.99 ± 0.28)]. Incremental cost/month for Allopathic treatment is 358%, Herbal treatment is 56%, Combination treatment is 187%. In Cost Effectiveness Analysis (CEA); Allopathic treatment (Incremental cost-effectiveness ratio/month: 1334.24), Herbal treatment (Incremental cost-effectiveness ratio/month: 936.41), Combination treatment (Incremental cost-effectiveness ratio/month: 1017.09). Due to lowest cost of Homeopathic treatment, cost of Homeopathic treatment was considered as a threshold value. In-direct cost/month of Allopathic treatment is PKR:593.33 ± 24.00 (USD:3.64 ± 0.15), Herbal treatment is PKR:307.84 ± 26.69 (USD:1.89 ± 0.16), Combination treatment is PKR:409.09 ± 45.63 (USD:2.51 ± 0.28) and Homoeopathic treatment is PKR:300.00 ± 26.39 (USD:1.84 ± 0.16).ConclusionThe most cost-effective is treatment is Homeopathic; Herbal treatment is second most cost-effective option for the treatment of PCOS. Lowest direct and indirect costs and short treatment duration collaboratively lessen the %incremental cost per year and incremental cost effectiveness ratio per year.

Prediction of synergistic gemcitabine-based combination treatment through a novel tumor stemness biomarker NANOG in pancreatic cancer.

Gemcitabine remains a first-class chemotherapeutic drug for pancreatic cancer. However, due to the rapid development of gemcitabine resistance in pancreatic cancer, gemcitabine alone or in combination with other anti-cancer drugs only showed limited effect in the clinic. It is extremely challenging to effectively and efficiently determine the optimal drug regimens. Thus, identification of appropriate prediction biomarkers is critical for the rational design of gemcitabine-based therapeutic options. Herein, a pancreatic cancer stem cell (PCSC) model exhibiting chemoresistance to gemcitabine was used to test the activity of clinical cancer drugs in the presence or absence of gemcitabine. As determined by combinatorial treatment, several types of drugs resensitized gemcitabine-resistant PCSCs to gemcitabine, with sorafenib (EGFR inhibitor)/gemcitabine and sunitinib (TBK1 inhibitors)/gemcitabine drug combinations being the most preferred treatments for PCSCs. Following the validation of the PCSC model by an antibody array test of 15-gene expression of stemness biomarkers, NANOG showed markedly different expression in PCSCs compared to the parental cells. From comprehensive analysis of stem cell index versus combination index, a stemness-related correlation model was successfully constructed to demonstrate the correlation between NANOG expression and synergism. Cancer cell stemness was ascertained to be highly relevant to NANOG overexpression that can be abrogated by synergized gemcitabine-drug combinations. Therefore, NANOG works as a therapeutic biomarker for predicating efficient combinatorial treatment of gemcitabine in pancreatic cancer.

Combined treatment of submacular hemorrhage with low-dose subretinal recombinant tissue plasminogen activator and intravitreal conbercept

BackgroundPars Plana Vitrectomy (PPV) combined with subretinal injection of low-dose recombinant tissue plasminogen activator (rt-PA) and intravitreal injection of Conbercept as a novel therapy for submacular hemorrhage (SMH) requires evaluation.MethodsIn a retrospective interventional clinical study, 14 eyes of 14 patients with SMH underwent PPV along with rt-PA (subretinal) and Conbercept (intravitreal) injections. The main outcomes included best-corrected visual acuities (BCVAs), degrees of blood displacement, and adverse events. All patients completed at least 6-month follow-up visits.ResultsMean BCVAs significantly improved at 7 days (22.29 ± 15.35), 1 month (30.71 ± 16.42), 3 months (38.29 ± 13.72), 4 months (38.86 ± 14.15), and 6 months (41.21 ± 14.91) post-treatment compared to baseline (16.36 ± 13.97) (F = 12.89, P = 0.004). The peak improvement in BCVAs occurred at 6 months postoperatively. The procedure effectively eliminated subfoveal hemorrhages in all eyes, with clots removal and absorption occurring within one month and complete regression by 3-month follow-up visits. Postoperatively, two cases of AMD resulted in discoid scars on the fundus. No instances of rt-PA-related retinal toxicity were observed during the follow-up period.ConclusionThe combined approach of PPV with low-dose rt-PA and anti-VEGF shows promise in enhancing both vision and anatomical structure in SMH therapy. Individualized treatment plans tailored to the primary disease should be developed to optimize visual prognoses.Trial registrationRetrospectively registered No.ChiCTR2100053034. Registration date: 10/11/2021.

Oncolytic virotherapy augments self-maintaining natural killer cell line cytotoxicity against neuroblastoma

BackgroundNeuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death.MethodsWe utilized MYCN amplified and non-amplified neuroblastoma cell lines, the IL-12 expressing oHSV, M002, and the human NK cell line, NK-92 MI. We assessed the cytotoxicity of NK cells against neuroblastoma with and without M002 infection, the effects of M002 on NK cell priming, and the impact of M002 and priming on the migratory capacity and CD107a expression of NK cells. To test clinical applicability, we then investigated the effects of M002 and NK cells on neuroblastoma in vivo.ResultsNK cells were more attracted to neuroblastoma cells that were infected with M002. There was an increase in neuroblastoma cell death with the combination treatment of M002 and NK cells both in vitro and in vivo. Priming the NK cells enhanced their cytotoxicity, migratory capacity and CD107a expression.ConclusionsTo the best of our knowledge, these investigations are the first to demonstrate the effects of an oncolytic virus combined with self-maintaining NK cells in neuroblastoma and the priming effect of neuroblastoma on NK cells. The current studies provide a deeper understanding of the relation between NK cells and neuroblastoma and these data suggest that oHSV increases NK cell cytotoxicity towards neuroblastoma.

Effect of Organic Sources of Nutrients and Bio Inoculants on Diversity of Microbes in Chickpea (Cicer arietinum L.)

A field experiment was conducted during two consecutive seasons of 2022-23 and 2023-2024 at Research Farm, Department of environmental science, college of Sehore, Mansarovar Global university Sehore (MP). The experiment was laid out in a split plot design with sixteen treatment combinations and replicated thrice. The study on the effect of organic sources of nutrient and bio-inoculants on diversity of microbe under chickpea. It is clear from the data that the highest microbial cells count like Rhizobium (16.43 x 106 cfu/g soil) (cfu- colony forming unit), PSB (Phosphate solubilizing bacteria) (19.03 x 106 cfu/g soil) was recorded under application of vermicompost @ 2 t ha-1 followed by FYM (farm yard manure) @ 5 t ha-1 along with Rhizobium and PSB (12.25 x 106 cfu/g soil) and (17.72 x 106 cfu/g soil), respectively. Whereas, highest fungi and actinomycetes count were observed under FYM @ 5 t ha-1 in combination with bio-inoculants and recorded 41.30 x 104 cfu/g and 12.92 x 103 cfu/g soil, respectively followed by vermicompost @ 2 t ha-1 with same inoculants. Whereas the lowest population of fungi was recorded under control along with combined application of bio-fertilizers (29.23 x 104 cfu/g and 7.25 x 103 cfu/g soil).