Hepatitis C virus (HCV)–associated kidney injury can affect both the glomeruli and the renal interstitium. The aim of this single-center, prospective real-world study involving HCV patients was to assess longitudinal changes in liver and kidney parameters during HCV treatment and to examine how renal function and urine findings evolved in those with kidney manifestations prior to therapy. In total, 217 patients treated for HCV-infection were enrolled for the study. Renal abnormalities were defined as either s-creatinine above the normal limit (male > 100 µmol/l, female > 90 µmol/l), or estimated glomerular filtration rate (eGFR) below < 60 ml/min/ 1.73 m2, or number of urine red blood cells above the normal (U–erythrocytes ≥ 20 × 10(E6)/l), or tubular proteinuria above the normal (U–α 1-microglobulin, UA1M, ≥ 12 mg/l), or glomerular proteinuria above the normal (U–albumin/creatinine ratio, UACR, in men ≥ 2.5 mg/mmol, in women ≥ 3.5 mg/mmol) levels in a spot urine test. Forty patients (20

We aimed to analyze the expression of cell-cycle regulation markers – minichromosome maintenance protein 2 (MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) and tumor-infiltrating lymphocytes (TILs) in pre-treatment core-biopsy samples of advanced breast carcinomas (ABC) in correlation with known predictive and prognostic factors. Consecutive breast cancer patients (n=398) treated during 2015-2019 were retrospectively analyzed. ABC was defined either as the first indication for locally recurrent, locally advanced or metastatic disease. TIL levels were evaluated of invasive tumor samples, and high expression was defined as TILs >15%. Immunohistochemistry was performed to analyze the expression of MCM2, Ki-67, Cyclin A and PHH3, which were correlated with the following clinicopathological parameters: clinical TNM, tumor grade, biological subtype, TILs, treatment type (chemotherapy-containing or non-chemotherapy). Univariate and multivariate analyses were used to assess factors associated with disease-free survival (DFS) and overall survival (OS). The multivariate analysis showed that patients with higher TIL levels had an improved 3-year DFS compared with those with low TIL levels, (79.5% vs. 63.7%, HR = 0.52, 95% CI = 0.32–0.78, p = 0.005), which may imply using the biomarkers to indicate initial treatment selection at the advanced stage. The effect was the most pronounced for triple-negative breast cancer (TNBC), and higher for HER2+ than hormone receptor positive breast cancer (HR+). Hormone receptor negative tumors showed significantly higher expression of the studied cell-cycle regulation markers Ki-67, MCM2 and Cyclin A compared with HR+ breast cancer, with TNBC showing the highest activity. Ki-67 and MCM2 were significantly associated with worse prognosis in HR+ breast cancer (p = 0.03; p = 0.04). Treatment type (chemotherapy vs. non-chemotherapy) as the initial treatment at the advanced stage influenced the 3-year DFS and OS in patients with high TIL levels in all molecular breast cancer subtypes. For those with low levels of TILs the difference was statistically non-significant. Our study showed that TIL and cell cycle marker testing could help to identify patients with more aggressive tumor types and the requirement of more aggressive treatment upfront. The proposed biomarker testing can help in selecting the appropriate treatment for increased disease-free survival. Citation Format: Sauli Vuoti, Minna Saari, Kumar Narasimha, Kai Reinikainen. Association of baseline tumor-infiltrating lymphocytes and cell-cycle regulation markers on prognosis and mortality in patients with advanced breast cancer according to tumor characteristics and treatment type [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-13.

Drug therapy causes immune cell depletion in multiple myeloma patients at an age when cell regenerative capacity is usually decreased. Successful regeneration of vital immune cells requires the recovery of both quantity and quality of immune cell subclasses. Although immune cell numbers eventually rebound after a treatment, it is unclear whether overall compositional diversity is recovered. This might limit treatment options at later treatment lines, or complicate treatment with future immune therapies, and lead to suboptimal treatment outcomes. In addition, the influence of different first line treatment combinations on immune cell diversity in multiple myeloma has not been systematically evaluated. We investigated the regeneration of immune cell complexity using mass cytometry and T cell receptor sequencing by comparing peripheral blood mononuclear cells from multiple myeloma patients coming off different first line treatment combinations at 6, 12 and 18 months after start of maintenance therapy. Our study showed changes in patients' CD4+ and CD8+T cells regardless of the type of the initial treatment regimen. Recovery of CD4+ naive T cells was incomplete even after 18 months, but the highest rate of recovery was achieved when anti-CD38-containing combinations were used as the initial treatment. The degree of recovery was generally higher among CD8+ T cells regardless of the type of first line therapy. Natural killer cells (NK cells), dendritic cells and monocytes remained largely unaffected with all treatment combinations, with differences seen mainly at the rate of recovery. Similarly as for T cells, the amount of B cells also decreased, but their diversity remained notably altered even at 18 months, showing strong dependence on the type of therapy. The highest rate of recovery and diversity for B cells was achieved with anti-CD38-containing treatment regimens. The type of maintenance treatment also influenced the extent and rate of recovery. Our data suggests that CD4 and B cells are more prone to permanent changes with specific treatment combinations, whereas other cell types recover to a larger extent. This data may be used to better understand the long-term consequences of initial treatment regimen selection, and provide support how to influence and maintain immune cell composition and diversity. The data may inform sequencing different therapies with the purpose of extending progression-free survival and enhanced disease control.

Most cases of keratinocyte cancer can be treated effectively with surgery. However, survival is reduced in patients with advanced disease. This retrospective cohort study evaluated overall survival of patients with invasive keratinocyte cancers, and high-risk features for progression of the disease and mortality in Finnish patients in a real-world setting. A total of 43,143 patients with keratinocyte cancer types of basal cell carcinoma and 10,380 with cutaneous squamous cell carcinoma were identified nationwide. More detailed patient records were available for a subset of patients (basal cell carcinoma n = 5,020 and cutaneous squamous cell carcinoma n = 1,482) from a regional database. Fifty percent of patients with advanced cutaneous squamous cell carcinoma died approximately 4.5 years after diagnosis. Multivariable models suggested that risk factors for keratinocyte cancer progression were male sex, presence of comorbidities, immunosuppression, and pre-cancerous lesions, while risk factors for disease-specific mortality were advanced disease stage with immunosuppression, other malignancies, and consecutive surgical excisions. These results suggest that identifying patient and tumour factors associated with poor disease outcome could be important when determining appropriate treatment and follow-up; however, further studies are necessary.

Background Hepatitis C virus (HCV) is common among individuals in opioid agonist therapy (OAT). HCV treatment has previously been unavailable for most HCV positive OAT patients in Finland. The removal of treatment restrictions and attempts to reach HCV elimination goals have increased the number of OAT patients needing HCV treatment. The objectives of this study were 1) to characterize Finnish HCV positive OAT patients and evaluate their eligibility for HCV treatment at addiction service units, and 2) to retrospectively review the outcomes of treated patients. Methods The study focused on HCV positive OAT patients ( n = 235). Demographics and clinical parameters were retrospectively reviewed using the patients’ medical records. The eligibility of providing HCV treatment to patients at addiction service units were evaluated based on patients’ clinical characteristics, such as liver function and patterns of substance use. The outcomes of patients receiving HCV treatment were reviewed. Results Of HCV antibody positive OAT patients, 75% had chronic HCV. Of 103 HCV patients screened for liver fibrosis either with Fibroscan or APRI (aspartate aminotransferase to platelet ratio index), 83 patients (81%) had no indication of severe liver damage. Point of care (POC) HCV tests were used for 46 patients to lower the threshold of attending laboratory testing. All patients preferred POC testing to conventional blood testing. Twenty patients had received HCV treatment, 19 completed the treatment and achieved sustained virologic response (SVR) at the end of the treatment. Of the 18 patients available for evaluation of SVR at 12 weeks after the treatment (SVR12), 17 achieved SVR12. Conclusions The integrated model consisting of HCV diagnostics and treatment at the addiction service unit was successfully implemented within normal OAT practice.

Chronic kidney disease (CKD) is one of the most well-known extrahepatic manifestations caused by hepatitis C infection (HCV). CKD is typically discovered at a late stage. HCV-nephropathy may show different histopathologic patterns, as both glomerular and tubulointerstitial damage have been described. Identification of patients with early renal manifestations would be beneficial to provide treatment and avoid progression to CKD. The observational prospective single-center HCVKID study assessed the prevalence of early renal manifestations in patients with chronic HCV and compared these patients with HCV-negative healthy controls cross-sectionally. HCV-positive patients with and without renal manifestations were also compared to define biomarkers suitable for identifying early manifestations in standard clinical practice. Tubular proteinuria as judged by urine α 1-microglobulin was the most common early renal manifestation found in 11% in HCV-positive patients, followed by hematuria in 8%. Kidney filtration was statistically significantly lower among HCV-positive patients with renal manifestation according to any calculation method. There were no significant differences in duration of infection or stage of liver fibrosis between patients with or without renal manifestations. Tubular cell damage may be the earliest sign of renal dysfunction caused by HCV. Complement activation also correlates with the dysfunction, indicating of contribution to HCV-induced renal manifestations even in their early phase.

Integrase inhibitors appear to increase body weight, but paradoxically some data indicate that raltegravir (RAL) may decrease liver fat. Our objective was to study the effects of switching from a protease inhibitor (PI) or efavirenz (EFV) to RAL on liver fat, body composition, and metabolic parameters among people living with HIV (PLWH) with high risk for nonalcoholic fatty liver disease (NAFLD). We randomized overweight PLWH with signs of metabolic syndrome to switch a PI or EFV to RAL (n = 19) or to continue unchanged antiretroviral therapy (control, n = 24) for 24 weeks. Liver fat was measured by magnetic resonance spectroscopy (MRS), body composition by magnetic resonance imaging, and bioimpedance analysis; subcutaneous fat biopsies were obtained. Median (interquartile range) liver fat content was normal in RAL 2.3% (1.1-6.0) and control 3.1% (1.6-7.3) group at baseline. Liver fat and visceral adipose tissue remained unchanged during the study. Body weight [from 85.9 kg (76.1-97.7) to 89.3 (78.7-98.7), p = 0.019], body fat mass [from 20.3 kg (14.6-29.7) to 22.7 (17.0-29.7), p = 0.015], and subcutaneous adipose tissue (SAT) volume [from 3979 mL (2068-6468) to 4043 (2206-6433), p = 0.048] increased, yet, adipocyte size [from 564 pL (437-733) to 478 (423-587), p = 0.019] decreased in RAL but remained unchanged in control group. Circulating lipids and inflammatory markers improved in RAL compared to control group. The median liver fat measured by MRS was unexpectedly within normal range in this relatively small study population with presumably high risk for NAFLD contradicting high prevalence of NAFLD reported with other methods. Despite weight gain, increase in SAT together with decreased adipocyte size and reduced inflammation may reflect improved adipose tissue function. Clinical Trial Registration number: NCT03374358.

e15599 Background: Targeting cancer cell metabolism has gained attention as a future strategy to fight cancer. A characteristic of tumor cells is the elevated aerobic glycolysis for energy production. It has been shown that 2-deoxy-D-glucose (2DG) inhibits glycolysis and induces apoptotic cell death in different tumor types. The anti-diabetic drug metformin has been used in combination to enhance the inhibitory effect. So far, the attempts to combine both compounds in a clinical setting have been limited by the requirement of concentrations higher than those accessible in blood plasma of human beings. Deep eutectic solvents (DES) are solvent mixtures prepared from hydrogen bond donors and acceptors, wherein pharmaceutically active compounds can also be one of the components. Besides having unique physicochemical properties, DESs have been reported to demonstrate or enhance anticancer properties. Methods: We developed a DES mixture from 2DG and MET using a method based in mechanical grinding. We investigated the anticancer activity of conventional and DES mixtures of MET and 2DG, and used the mixtures to inhibit the growth, migration and invasion of cancer cells, and induce cell cycle arrest in vitro. Results: MET and 2DG, alone and in combination, induced apoptosis in the H460, SKOV-3, MDA-MB-231 and HCC1806 (TNBC) cell lines. Induction of apoptosis was further quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. DES mixtures had the highest impact on cell viability, exceeding the effect of 2DG/MET as single agents or combinations at all clinically relevant concentrations. The DES mixture with the lowest concentration to induce apoptosis consisted of 100 µM 2DG and 200 µM MET. A conventional solution with similar concentrations showed no activity. Conclusions: We developed a DES from 2DG/MET, which significantly reduced the viability of several types of cancer cells, surpassing the effect of single components or mixtures. The DES does not necessitate the use of additional solvents and could be used to develop clinical applications for targeting cancer cell metabolism.

Background: There is no multicenter clinical study about cytokine-induced killer (CIK) cells in lung cancer.This randomized, multicenter trial was designed to evaluate the efficacy of CIK cell immunotherapy combination with chemotherapy in patients with advanced squamous non-small-cell lung cancer (NSCLC).Methods: In this phase II trial, 90 patients with untreated, stage IIIB/IV squamous NSCLC were randomized to autologous CIK cell immunotherapy plus gemcitabine and cisplatin (CIK-CT group, n ¼ 45), or gemcitabine and cisplatin (CT group, n ¼ 45).The primary endpoint was progression-free survival (PFS) and secondary endpoint was overall survival (OS) evaluated by KaplaneMeier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model.Results: After a median follow-up of 29.3 months, the median PFS was 8.7 months (95% CI, 7.1 to 10.3) in the CIK-CT group and 4.0 months (95% CI, 3.1 to 5.0) in the CT group (HR, 0.26; 95% CI, 0.16 to 0.43; P < .001).The median OS was 21.0 months (95% CI, 17.8 to 24.2) in the CIK-CT group and 10.3 months (95% CI, 7.9 to 12.1) in the CT group (HR, 0.22; 95% CI, 0.13 to 0.40; P < .001).The objective response rate was 62.2% (95% CI, 47.9% to 76.5%) in the CIK-CT group and 31.1% (95% CI, 17.4% to 44.8%) in the CT group (P < .001).The adverse events of grade 3 or higher were 33.3% and 42.2% in the CIK-CT group and CT group, respectively.Conclusions: These data suggested that the addition of CIK cell immunotherapy to chemotherapy resulted in significantly longer PFS and OS than chemotherapy alone in patients with previously untreated, advanced squamous NSCLC.Clinical trial identification: NCT01631357.

e15598 Background: Intratumoral drug delivery in cancer treatment has shown to increase drug accumulation in tumors and decrease adverse effects of systemic therapies. The active agent is typically required to stay in contact with the tumor and thus attachment directly into the tumor or to the surrounding tissue is warranted. In addition, a long-acting release of the active drug is vital. Dendrimers are nano-sized, radially symmetric molecules with homogeneous and monodisperse structures, which can used to encapsulate drug molecules for controlled release with the aid of external stimuli at physiological pH. Methods: We prepared a dendrimeric drug delivery matrix based on a PEG-core. The model drug (5-fluorouracil or doxorubicin) was covalently bonded to the core. The release of the drug was observed up to 29 days in vitro. The outer shell of the matrix was partially modified to obtain a fast UV-curing and subsequent attachment to the tumor tissue utilizing interstitial photodynamic therapy. We compared the pharmacokinetics, tissue distribution and antitumor efficacy of conventional systemic therapy and the intratumoral therapy in xenograft-bearing mice. In addition, we monitored blood parameters and body weight of the animals for adverse effects. Results: The dendrimer matrix caused significantly greater inhibition of human hepatocellular carcinoma xenograft tumor growth when compared with systemic therapy, without increasing toxicity. The matrix enabled a significant increase in drug accumulation in tumors, and markedly extended the survival of mice compared with systemic treatments. A larger decrease in blood parameters as well as spleen weight was observed in the systemic therapy group especially when using 5-fluorouracil. Conclusions: Our study shows that the intratumoral treatment strategy based on a novel UV-curable dendrimer hydrogel matrix enhances antitumor activity by improving pharmacokinetics and drug accumulation and increases efficacy in comparison to conventional systemic therapy. These results highlight the potential use of dendrimer hydrogels in the treatment of hepatocellular carcinoma.

Adverse events occur in majority of patients receiving systemic cancer therapies. Intratumoral administration is a potential solution to limit these events by reducing systemic exposure while increasing local concentration in the tumor. The active agent is typically required to stay in contact with the tumor. This requires attachment directly into the tumor or to the surrounding tissue. Dendrimers are well-defined, multivalent molecules having branched structure of nanometer size, which can be used to form injectable gels. Dendrimers have been used to encapsulate and release drugs with the aid of external stimuli at physiological pH. We prepared a dendrimeric drug delivery matrix based on a PEG-core. The model drug (5-fluorouracil, docetaxel, capecitabine, cisplatin) was encapsulated in the matrix. The outer shell of the matrix was modified with photoreactive groups, injected inside the tumor, and attached to the tumor by activation of the photoreactive groups with the aid of interstitial photodynamic therapy. We compared the pharmacokinetics, tissue distribution and antitumor efficacy of conventional systemic therapy and the intratumoral therapy in xenograft-bearing mice. The tumor growth curve was plotted and tumor, spleen, lymph nodes, and lungs were collected at the study endpoint for further flow cytometry and histological analysis. The dendrimer-based therapy showed significantly decreased tumor growth rates over standard systemic therapies. Mice treated with the intratumoral dendrimer showed decreased toxicity when compared to those receiving systemic therapies. The matrix enabled a significant increase in drug accumulation in tumors, and markedly extended the survival of mice compared with conventional systemic treatments. Local sustained intratumoral systemic therapy is a potential strategy for improving treatment of solid tumors while minimizing adverse side effects. The photoreactive dendrimer matrix enhances antitumor activity by improving intratumoral drug accumulation and increases efficacy in comparison to conventional systemic therapies. These results highlight the potential use of photoreactive dendrimers in the treatment of several cancer types.

Chronic infection with hepatitis C virus (HCV) is associated with significant morbidity and all-cause mortality. Recent advances in treatment have made the disease curable for all patient groups, including those previously considered uncurable.1 To treat patients in need of care, those with chronic HCV must be identified with adequate testing methods. However, to conduct testing and subsequently refer patients to treatment, the relevant individuals must be first linked and attached to care. Finland's Hepatitis C Strategy has estimated that there are more than 30 000 persons infected with HCV living in Finland as of 2019 (Finland's Hepatitis C Strategy for 2017-2019, available online). By the end of 2018, 31 647 HCV-antigen-positive cases had been entered into Finland's National Infectious Diseases Register since the establishment of the register in 1998 (Infectious Diseases Register, accessed April 2020). In Finland, around 1150 persons are infected each year, and the disease burden is slowly increasing because the amount of treatment given has fallen behind the number of persons requiring treatment.2 In a recent meta-analysis by Fraser et al,3 it was suggested that the rate of treatment should be increased 200 times in Finland to reduce HCV prevalence to 30% by 2030. In a global review by Razavi et al,4 it was concluded that 80% of high-income countries are not on track to meet HCV elimination targets by 2030, and 67% are off track by at least 20 years. Immediate action to improve HCV screening and treatment globally was suggested to make HCV elimination attainable. Drug use has previously prevented the provision of treatment, but this barrier was lifted in 2018. A national strategy (Finland's Hepatitis C Strategy for 2017-2019, 2016) and national recommendation on the cascade of care2 determined that all persons should be tested and treated regardless of their drug user status. Finland has a very low population density of 39 people per square mile (15 people per square kilometer), which ranks 171st in the world and makes Finland one of the most sparsely populated countries of the European Union (World Population Review, 2020). For this reason, the national recommendation is to establish regional treatment plans and programs. South Karelia (population: 130 000) is region located by the Russian border, with the highest reported incidence for HCV in Finland (Infectious Diseases Register, accessed April 2020). This paper reviews the real-life outcome of the South Karelia Linkage to Care program, which combined data from the National Infectious Diseases Register and social registries to identify living HCV-antigen-positive persons still residing in the region. These persons were tracked down, contacted, and finally motivated for testing to identify individuals with chronic HCV and provide them with a treatment plan. In addition, the persons' data were entered into an electronic regional Hepatitis C register, and the experience gained in the program was used to create a regional cascade of care, in harmony with the global WHO goals. This retrospective real-world register analysis was approved by the committee of the Southern Karelia Central Hospital, decision number EKS/1392/13.01.05/2019. At the beginning of the project, national social welfare and infectious disease registers were used to identify all HCV-antigen-positive persons (name, social security number, address or other identification parameters) still residing in the area. In addition, the cause of death register was used to exclude those who had deceased. The second step was to check the HCV RNA status of those identified in the previous phase based on their medical records and to recognize patients who had already received treatment or were HCV RNA negative. Those whose HCV RNA status was unknown were contacted either by telephone, letter, or social media. Newspaper announcements and posters on various kinds of addiction service sites were also used to invite persons for testing if they had any suspicion of an HCV infection. If no contact information was found, persons using services relevant based on the missing individuals' medical records (opioid substitution therapy or needle exchange programs) were utilized to reach the missing individuals or forward the request to them. When the individuals were found, they were invited to visit the clinic so that a treatment plan could be prepared or their HCV RNA status determined if previously unknown. In addition, the individuals were provided with information about the disease and the change in treatment policies in Finland. Information about those who could not be reached by any method was provided to the local health centers based on their latest known residence to test them for HCV RNA later if they visited the health services. The regional cascade of care was adapted from the national recommendation. All health service providers (primary care, specialized hospital care, substance addiction, and social services) in the region were notified, enrolled in the program, and trained to provide information about the patients' right to get tested for their HCV antigen status as well as general information about the disease. Patient data collected from the medical records available in all of the sources were used to establish an electronic regional HCV registry. The demographic and clinical characteristics of the HCV-antigen-positive subjects are presented in Table 1. Male gender was more frequent among the population, and the median age was 40.7 years. Due to removal for the requirement to define the genotype, genotype had been defined from only 118 subjects and was similar to national prevalence (Finland's Hepatitis C Strategy for 2017-2019, available online). Fibroscan measurements were rare, as APRI, according to recommendations, APRI score (AST to Platelet Ratio Index) is used as the primary diagnostic method to investigate the state of liver health. In total, 97 patients had initiated treatment, of which 81 received SVR12. Thirteen patients were lost to follow-up or did not attend SVR12 testing. Seventy-four patients experienced a spontaneous recovery. Figure 1 summarizes the study results. In the beginning of the project, 525 persons with an HCV-antigen-positive status were identified as alive and still residing in the South Karelia region. Of those persons, 81 had been treated and 74 had experienced a spontaneous recovery. Totally, 370 people were identified as potentially HCV RNA positive and invited for either further testing if their HCV RNA status was unknown, or for treatment evaluation if they were found to be HCV RNA positive. Of these 370 individuals, some type of contact information was obtained for 339 individuals. Of these 339, a total of 220 individuals could be reached. Information on some of the individuals' HCV RNA status was obtained from their medical records without establishing contact with the person. Additional testing was conducted on a proportion of the individuals whose HCV RNA status was previously unclear or who were determined to continue high-risk behavior such as IV drug use. Fifty of the individuals who had been referred to the laboratory did not attend testing and contact with them was lost. Finally, at least 284 individuals were confirmed to be HCV RNA positive and remained untreated at the time. All of those motivated to start treatment received a treatment plan. At the end of the project, 220 out of the potential 370 HCV RNA-positive individuals were linked to care. Eighty-six individuals could either not be reached or had no record of their HCV RNA status. HCV RNA status was determined for 442 individuals out of the 525 HCV-antigen-positive people identified at the beginning of the project. Our program aimed to clarify the HCV RNA status of HCV-antigen-positive individuals living in the Southern Karelia region and link all traced HCV RNA-positive people to care. At the end of the project, the HCV RNA status of 84% of the HCV-antigen-positive population had been determined. In addition, 59% of the patients were linked to care. Lack of motivation to get tested and start treatment was identified as the biggest barrier for linking patients to care. Persons identified as actively using drugs emerged as the subpopulation requiring more extensive psychosocial interventions to achieve attachment to care. Ninety individuals in our cohort reported having used IV drugs during the previous year. Individuals aged 20 to 25, 25 to 30, and 30 to 35 years were less motivated to start treatment in comparison with other age groups. The barriers for linking individuals to care involved many traditional aspects reported elsewhere.5-9 Disease awareness was generally low among the individuals, with some of them commenting that since they had no symptoms, they were not motivated to start treatment. Most individuals still thought that drug abstinence was a requirement for receiving treatment and were not aware of direct-acting antivirals. Prejudices and previous negative experiences of using healthcare services were also frequently described. Fear of stigmatization was given as a reason by many of those individuals who were currently employed and not actively using drugs. They reported wanting to avoid additional entries on HCV in their medical records. By contrast, many were motivated to start treatment after receiving information about the current treatment policy and options as well as general information about the disease. Many had been waiting for an opportunity to be treated. Long geographical distances have traditionally posed a challenge for healthcare in Finland and other sparsely populated countries. For this reason, networking within the healthcare system and collaboration between the service providers essential to reaching the goals even at a regional level. Primary health service providers would generally need additional resources to initiate HCV treatments because of a lack of centralized funding in Finland. For this reason, their contribution to this program was limited and not in harmony with the national recommendation. This program successfully established a cascade of care for linking, testing, and treating HCV-positive persons in the Southern Karelia region. An electronic HCV register was established and deemed essential for following and maintaining treatment goals and continuing to support those treated with regular follow-ups and counseling. Special thanks to Irene Dietrich and Lotta Krogius-Kurikka for their participation in and support for the project. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors do not have any conflicts or competing interests to declare. Conceptualization: Juha Kemppinen, Sauli Vuoti, Pekka Suomalainen Formal analysis: Juha Kemppinen, Hanna-Kaisa Anttila, Sauli Vuoti Writing – original draft: Sauli Vuoti, Hanna-Kaisa Anttila, Juha Kemppinen Writing – review and editing: Sauli Vuoti, Juha Kemppinen, Pekka Suomalainen All authors have read and approved the final version of the manuscript. Sauli Vuoti had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. The authors confirm that the data supporting the findings of this study are available within the article.

Cancer cell metabolism has been proposed as a new strategy to fight cancer. Elevated aerobic glycolysis of cancer cells for energy production provides a possibility for therapeutic intervention. 2-deoxy-D-glucose (2DG) and metformin (MET) have been used in combination to inhibit glycolysis and induce cell death in various tumour types. The required doses have exceeded that achievable in human plasma. Deep eutectic solvents (DES) are mixtures of solid compounds that form liquids due to a large depression of the melting point and possess unique properties such as pharmacological activity. DESs have been reported to demonstrate anticancer properties but have not previously been studied in vivo mouse models. We investigated the preclinical efficacy of targeting the tumour bioenergetic pathway using conventional and DES mixtures of MET and 2DG in MDA-MB-231 (human breast adenocarcinoma) and UFH-001 (triple-negative breast cancer) cells. We evaluated the in vitro anti-tumour activity of the individual components MET and 2DG and the DES mixture for comparison. In addition, we examined in vivo efficacy using xenograft mouse models. 2DG and MET alone were not sufficient to promote tumour cell death, reflecting the limited efficacy demonstrated in clinical trials. A combined use of 2DG and MET also failed to induce cell death. However, the DES mixture of 2DG and MET led to significant cell death associated with decrease in cellular ATP and sustained autophagy. DES mixtures had the highest impact on tumour cell viability, exceeding the effect of 2DG/MET as single agents or combinations at all clinically relevant concentrations. We developed a DES mixture from 2DG/MET, which significantly induced apoptosis of cancer cells, exceeding the effect of single components or conventional mixtures. Deprivation of tumour bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for human breast cancer tumours. The DES does not necessitate the use of toxic components or additional solvents and could be used to develop clinical applications for targeting breast cancer cell metabolism.

Hepatitis C infection is known to cause kidney derangements. HCV-related nephropathy may show different histopathologic patterns and both glomerular and tubulointerstitial damage have been described. Kidney injury may result from immune-mediated tissue damage or from direct effects of HCV and other, yet unknown mechanisms may be involved. HCV-related nephropathy may appear at any time during the natural history of HCV infection. Objective of the prospective, observational HCVKID-study is to assess the prevalence of renal manifestations among patients suffering from chronic HCV in Finland cross-sectionally, complemented by long-term analysis to identify changes from baseline.

Background: The Finnish population offers many advantages for evaluating the impact of anti-dementia medication on mortality in Alzheimer's disease (AD) due to broad range of individual-level data collected in national health and social care registries and the fact that Finland has one of the highest mortality rates for dementia globally. Objective: The aim of this study was to investigate the association of anti-dementia medication with 2-year risk of death and all-cause mortality in patients with AD. Methods: This was a retrospective, non-interventional registry study based on individual-level data using Finnish national health and social care registries. An incident cohort of 9,204 AD patients (first AD diagnosis in 2012) was formed from a population of 316,470 individuals >= 74 years of age. The main outcome measure was overall 2-year risk of death. Statistical modelling was used to assess mortality (Kaplan-Meier) and adjusted hazard ratios (HR) (Cox proportional hazard model). Results: Early start of anti-dementia medication (treatment started <= 3 months from AD diagnosis) reduced significantly the risk of all-cause death compared to AD patients who had late medication initiation (defined as treatment started >3 months from AD diagnosis/no medication; HR, 0.51; 95% confidence interval (CI), 0.46-0.57). Dementia was the most common recorded cause of death in both groups. Conclusion: This study places importance on early diagnosis of AD and subsequent early initiation of drug treatment in decreasing 2-year risk of death.

Cellulose offers a large renewable raw material base and can be chemically modified in a variety of ways to introduce new functionalities such as cationic charge, that are required in effective waste water treatment for any polymers. Cationic cellulose derivatives were synthesized using both conventional and novel methods from several commercially available cellulose pulps. The cationic derivatives were used as biobased flocculants to treat real-life wastewater samples in a head-to-head comparison with cationic polyacrylamides. A novel high-consistency, high shear mixing heterogeneous mixing method enables the preparation of cellulose derivatives without the use of solvent or high cost solubilization methods. When higher cationic charge is required, deep eutectic solvents can be used to modify cellulose. Both the molecular weight and charge of the cationic cellulose derivatives have a drastic influence on performance in water treatment applications. Flocculation experiments with real-life waste water samples revealed that cationic cellulose derivatives are able to effectively function as flocculants and fixatives, and even outperform commercial polyacrylamides. The highest achieved level of turbidity removal was 93.2%. Cationic cellulose derivatives provided good efficacy in sludge dewatering, Focused Beam Reflectance Measurement flocculation tests and anionic trash fixing, which are crucial properties for the pulp and paper industry.

[Article in J. Appl. Polym. Sci. 2017, 134, DOI: 10.1002/app.44801]In the article mentioned above, the authors wish to acknowledge that all experimental work presented in this paper was conducted at VTT.The authors apologize for any inconvenience caused.

Using softwood pulp as the starting material, the synthesis of regioselectively substituted mixed cellulose esters with varying degree of substitution and ratio of short/long chains was successfully completed. The structures of the cellulose esters were characterised. The impact of the structural changes and the degree of substitution of the cellulose esters on thermal properties and processability were investigated. The study shows that the sequential esterification is a promising modification route for cellulose to improve its thermal processability and mechanical properties without the use of external processing aids such as plasticisers. In particular, the hexanoate group in the C6 position on the cellulose backbone acts as an internal plasticiser and improves thermal processability and increases the strength and stiffness of the cellulose ester. The properties of sequentially esterified cellulose promote its practical use in plastics, coatings, films and drug delivery. Sequentially esterified cellulose hexanoate-acetate was used successfully in a coating formulation for the preparation of tablets and showed a stable extended release profile for three water-insoluble drugs in this context. The pH of the release medium had no notable effect on the release properties.